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[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid- to late-January. Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5–6 days, with an upper limit of around 11-14 days 2,5 , and delays from illness onset to laboratory confirmation added a further 10 days on average . Text: It is now 6 weeks since Chinese health authorities announced the discovery of a novel coronavirus 2019-nCoV causing a cluster of pneumonia cases in Wuhan, the major transport hub of central China. The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases .", "The earliest human infections had occurred by early December 2019, and a large wet market in central Wuhan was linked to most, but not all, of the initial cases . While evidence from the initial outbreak investigations seemed to suggest that 2019-nCoV could not easily spread between humans , it is now very clear that infections have been spreading from person to person . We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world.", "We recently estimated that more than 75,000 infections may have occurred in Wuhan as at 25 January 2020 , and increasing numbers of infections continue to be detected in other cities in mainland China and around the world. A number of important characteristics of 2019-nCoV infection have already been identified, but in order to calibrate public health responses we need improved information on transmission dynamics, severity of the disease, immunity, and the impact of control and mitigation measures that have been applied to date. Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days .", "Infections with 2019-nCoV can spread from person to person, and in the earliest phase of the outbreak the basic reproductive number was estimated to be around 2.2, assuming a mean serial interval of 7.5 days . The serial interval was not precisely estimated, and a potentially shorter mean serial interval would have corresponded to a slightly lower basic reproductive number. Control measures and changes in population behaviour later in January should have reduced the effective reproductive number.", "Control measures and changes in population behaviour later in January should have reduced the effective reproductive number. However, it is too early to estimate whether the effective reproductive number has been reduced to below the critical threshold of 1 because cases currently being detected and reported would have mostly been infected in mid-to late-January. Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average .", "Average delays between infection and illness onset have been estimated at around 5-6 days, with an upper limit of around 11-14 days , and delays from illness onset to laboratory confirmation added a further 10 days on average . Chains of transmission have now been reported in a number of locations outside of mainland China. Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries.", "Within the coming days or weeks it will become clear whether sustained local transmission has been occurring in other cities outside of Hubei province in China, or in other countries. If sustained transmission does occur in other locations, it would be valuable to determine whether there is variation in transmissibility by location, for example because of different behaviours or control measures, or because of different environmental conditions. To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur.", "To address the latter, virus survival studies can be done in the laboratory to confirm whether there are preferred ranges of temperature or humidity for 2019-nCoV transmission to occur. In an analysis of the first 425 confirmed cases of infection, 73% of cases with illness onset between 12 and 22 January reported no exposure to either a wet market or another person with symptoms of a respiratory illness . The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring .", "The lack of reported exposure to another ill person could be attributed to lack of awareness or recall bias, but China's health minister publicly warned that pre-symptomatic transmission could be occurring . Determining the extent to which asymptomatic or pre-symptomatic transmission might be occurring is an urgent priority, because it has direct implications for public health and hospital infection control. Data on viral shedding dynamics could help in assessing duration of infectiousness.", "Data on viral shedding dynamics could help in assessing duration of infectiousness. For severe acute respiratory syndrome-related coronavirus SARS-CoV , infectivity peaked at around 10 days after illness onset , consistent with the peak in viral load at around that time . This allowed control of the SARS epidemic through prompt detection of cases and strict isolation.", "This allowed control of the SARS epidemic through prompt detection of cases and strict isolation. For influenza virus infections, virus shedding is highest on the day of illness onset and relatively higher from shortly before symptom onset until a few days after onset . To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS.", "To date, transmission patterns of 2019-nCoV appear more similar to influenza, with contagiousness occurring around the time of symptom onset, rather than SARS. Transmission of respiratory viruses generally happens through large respiratory droplets, but some respiratory viruses can spread through fine particle aerosols , and indirect transmission via fomites can also play a role. Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance.", "Coronaviruses can also infect the human gastrointestinal tract , and faecal-oral transmission might also play a role in this instance. The SARS-CoV superspreading event at Amoy Gardens where more than 300 cases were infected was attributed to faecal-oral, then airborne, spread through pressure differentials between contaminated effluent pipes, bathroom floor drains and flushing toilets . The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 .", "The first large identifiable superspreading event during the present 2019-nCoV outbreak has apparently taken place on the Diamond Princess cruise liner quarantined off the coast of Yokohama, Japan, with at least 130 passengers tested positive for 2019-nCoV as at 10 February 2020 . Identifying which modes are important for 2019-nCoV transmission would inform the importance of personal protective measures such as face masks and specifically which types and hand hygiene. The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia.", "The first human infections were identified through a surveillance system for pneumonia of unknown aetiology, and all of the earliest infections therefore had Modelling studies incorporating healthcare capacity and processes pneumonia. It is well established that some infections can be severe, particularly in older adults with underlying medical conditions , but based on the generally mild clinical presentation of 2019-nCoV cases detected outside China, it appears that there could be many more mild infections than severe infections. Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required.", "Determining the spectrum of clinical manifestations of 2019-nCoV infections is perhaps the most urgent research priority, because it determines the strength of public health response required. If the seriousness of infection is similar to the 1918/19 Spanish influenza, and therefore at the upper end of severity scales in influenza pandemic plans, the same responses would be warranted for 2019-nCoV as for the most severe influenza pandemics. If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly.", "If, however, the seriousness of infection is similar to seasonal influenza, especially during milder seasons, mitigation measures could be tuned accordingly. Beyond a robust assessment of overall severity, it is also important to determine high risk groups. Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children .", "Infections would likely be more severe in older adults, obese individuals or those with underlying medical conditions, but there have not yet been reports of severity of infections in pregnant women, and very few cases have been reported in children . Those under 18 years are a critical group to study in order to tease out the relative roles of susceptibility vs severity as possible underlying causes for the very rare recorded instances of infection in this age group. Are children protected from infection or do they not fall ill after infection?", "Are children protected from infection or do they not fall ill after infection? If they are naturally immune, which is unlikely, we should understand why; otherwise, even if they do not show symptoms, it is important to know if they shed the virus. Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity.", "Obviously, the question about virus shedding of those being infected but asymptomatic leads to the crucial question of infectivity. Answers to these questions are especially pertinent as basis for decisions on school closure as a social distancing intervention, which can be hugely disruptive not only for students but also because of its knock-on effect for child care and parental duties. Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers.", "Very few children have been confirmed 2019-nCoV cases so far but that does not necessarily mean that they are less susceptible or that they could not be latent carriers. Serosurveys in affected locations could inform this, in addition to truly assessing the clinical severity spectrum. Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera.", "Another question on susceptibility is regarding whether 2019-nCoV infection confers neutralising immunity, usually but not always, indicated by the presence of neutralising antibodies in convalescent sera. Some experts already questioned whether the 2019-nCoV may behave similarly to MERS-CoV in cases exhibiting mild symptoms without eliciting neutralising antibodies . A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease .", "A separate question pertains to the possibility of antibody-dependent enhancement of infection or of disease . If either of these were to be relevant, the transmission dynamics could become more complex. A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV.", "A wide range of control measures can be considered to contain or mitigate an emerging infection such as 2019-nCoV. Internationally, the past week has seen an increasing number of countries issue travel advisories or outright entry bans on persons from Hubei province or China as a whole, as well as substantial cuts in flights to and from affected areas out of commercial considerations. Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions.", "Evaluation of these mobility restrictions can confirm their potential effectiveness in delaying local epidemics , and can also inform when as well as how to lift these restrictions. If and when local transmission begins in a particular location, a variety of community mitigation measures can be implemented by health authorities to reduce transmission and thus reduce the growth rate of an epidemic, reduce the height of the epidemic peak and the peak demand on healthcare services, as well as reduce the total number of infected persons . A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures.", "A number of social distancing measures have already been implemented in Chinese cities in the past few weeks including school and workplace closures. It should now be an urgent priority to quantify the effects of these measures and specifically whether they can reduce the effective reproductive number below 1, because this will guide the response strategies in other locations. During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic .", "During the 1918/19 influenza pandemic, cities in the United States, which implemented the most aggressive and sustained community measures were the most successful ones in mitigating the impact of that pandemic . Similarly to international travel interventions, local social distancing measures should be assessed for their impact and when they could be safely discontinued, albeit in a coordinated and deliberate manner across China such that recrudescence in the epidemic curve is minimised. Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time.", "Mobile telephony global positioning system GPS data and location services data from social media providers such as Baidu and Tencent in China could become the first occasion when these data inform outbreak control in real time. At the individual level, surgical face masks have often been a particularly visible image from affected cities in China. Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons.", "Face masks are essential components of personal protective equipment in healthcare settings, and should be recommended for ill persons in the community or for those who care for ill persons. However, there is now a shortage of supply of masks in China and elsewhere, and debates are ongoing about their protective value for uninfected persons in the general community. The Table summarises research gaps to guide the public health response identified.", "The Table summarises research gaps to guide the public health response identified. In conclusion, there are a number of urgent research priorities to inform the public health response to the global spread of 2019-nCoV infections. Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations.", "Establishing robust estimates of the clinical severity of infections is probably the most pressing, because flattening out the surge in hospital admissions would be essential if there is a danger of hospitals becoming overwhelmed with patients who require inpatient care, not only for those infected with 2019-nCoV but also for urgent acute care of patients with other conditions including those scheduled for procedures and operations. In addressing the research gaps identified here, there is a need for strong collaboration of a competent corps of epidemiological scientists and public health workers who have the flexibility to cope with the surge capacity required, as well as support from laboratories that can deliver on the ever rising demand for diagnostic tests for 2019-nCoV and related sequelae. The readiness survey by Reusken et al.", "The readiness survey by Reusken et al. in this issue of Eurosurveillance testifies to the rapid response and capabilities of laboratories across Europe should the outbreak originating in Wuhan reach this continent . In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally.", "In the medium term, we look towards the identification of efficacious pharmaceutical agents to prevent and treat what may likely become an endemic infection globally. Beyond the first year, one interesting possibility in the longer term, perhaps borne of wishful hope, is that after the first few epidemic waves, the subsequent endemic re-infections could be of milder severity. Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold.", "Particularly if children are being infected and are developing immunity hereafter, 2019-nCoV could optimistically become the fifth human coronavirus causing the common cold. None declared." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]

[ "Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms.", "The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways.", "In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations.", "Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.", "This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases. Text: The prevalence of chronic airway inflammatory disease is increasing worldwide especially in developed nations GBD 2015 Chronic Respiratory Disease Collaborators, 2017 Guan et al., 2018 . This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath.", "This disease is characterized by airway inflammation leading to complications such as coughing, wheezing and shortness of breath. The disease can manifest in both the upper airway such as chronic rhinosinusitis, CRS and lower airway such as asthma and chronic obstructive pulmonary disease, COPD which greatly affect the patients' quality of life Calus et al., 2012; Bao et al., 2015 . Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease.", "Treatment and management vary greatly in efficacy due to the complexity and heterogeneity of the disease. This is further complicated by the effect of episodic exacerbations of the disease, defined as worsening of disease symptoms including wheeze, cough, breathlessness and chest tightness Xepapadaki and Papadopoulos, 2010 . Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 .", "Such exacerbations are due to the effect of enhanced acute airway inflammation impacting upon and worsening the symptoms of the existing disease Hashimoto et al., 2008; Viniol and Vogelmeier, 2018 . These acute exacerbations are the main cause of morbidity and sometimes mortality in patients, as well as resulting in major economic burdens worldwide. However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers.", "However, due to the complex interactions between the host and the exacerbation agents, the mechanisms of exacerbation may vary considerably in different individuals under various triggers. Acute exacerbations are usually due to the presence of environmental factors such as allergens, pollutants, smoke, cold or dry air and pathogenic microbes in the airway Gautier and Charpin, 2017; Viniol and Vogelmeier, 2018 . These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath.", "These agents elicit an immune response leading to infiltration of activated immune cells that further release inflammatory mediators that cause acute symptoms such as increased mucus production, cough, wheeze and shortness of breath. Among these agents, viral infection is one of the major drivers of asthma exacerbations accounting for up to 80-90% and 45-80% of exacerbations in children and adults respectively Grissell et al., 2005; Xepapadaki and Papadopoulos, 2010; Jartti and Gern, 2017; Adeli et al., 2019 . Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 .", "Viral involvement in COPD exacerbation is also equally high, having been detected in 30-80% of acute COPD exacerbations Kherad et al., 2010; Jafarinejad et al., 2017; Stolz et al., 2019 . Whilst the prevalence of viral exacerbations in CRS is still unclear, its prevalence is likely to be high due to the similar inflammatory nature of these diseases Rowan et al., 2015; Tan et al., 2017 . One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection .", "One of the reasons for the involvement of respiratory viruses' in exacerbations is their ease of transmission and infection . . In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 .", "In addition, the high diversity of the respiratory viruses may also contribute to exacerbations of different nature and severity Busse et al., 2010; Costa et al., 2014; Jartti and Gern, 2017 . Hence, it is important to identify the exact mechanisms underpinning viral exacerbations in susceptible subjects in order to properly manage exacerbations via supplementary treatments that may alleviate the exacerbation symptoms or prevent severe exacerbations. While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation.", "While the lower airway is the site of dysregulated inflammation in most chronic airway inflammatory diseases, the upper airway remains the first point of contact with sources of exacerbation. Therefore, their interaction with the exacerbation agents may directly contribute to the subsequent responses in the lower airway, in line with the \"United Airway\" hypothesis. To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway.", "To elucidate the host airway interaction with viruses leading to exacerbations, we thus focus our review on recent findings of viral interaction with the upper airway. We compiled how viral induced changes to the upper airway may contribute to chronic airway inflammatory disease exacerbations, to provide a unified elucidation of the potential exacerbation mechanisms initiated from predominantly upper airway infections. Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s .", "Despite being a major cause of exacerbation, reports linking respiratory viruses to acute exacerbations only start to emerge in the late 1950s . ; with bacterial infections previously considered as the likely culprit for acute exacerbation Stevens, 1953; Message and Johnston, 2002 . However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 .", "However, with the advent of PCR technology, more viruses were recovered during acute exacerbations events and reports implicating their role emerged in the late 1980s Message and Johnston, 2002 . Rhinovirus RV and respiratory syncytial virus RSV are the predominant viruses linked to the development and exacerbation of chronic airway inflammatory diseases Jartti and Gern, 2017 . Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 .", "Other viruses such as parainfluenza virus PIV , influenza virus IFV and adenovirus AdV have also been implicated in acute exacerbations but to a much lesser extent Johnston et al., 2005; Oliver et al., 2014; Ko et al., 2019 . More recently, other viruses including bocavirus BoV , human metapneumovirus HMPV , certain coronavirus CoV strains, a specific enterovirus EV strain EV-D68, human cytomegalovirus hCMV and herpes simplex virus HSV have been reported as contributing to acute exacerbations . The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 .", "The common feature these viruses share is that they can infect both the upper and/or lower airway, further increasing the inflammatory conditions in the diseased airway Mallia and Johnston, 2006; Britto et al., 2017 . Respiratory viruses primarily infect and replicate within airway epithelial cells . During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche .", "During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche . . In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells.", "In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of activation of an antiviral state and infiltration of antiviral effector cells. This eventually results in the resolution of the inflammatory response and clearance of the viral infection Vareille et al., 2011; Braciale et al., 2012 . However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 .", "However, in a chronically inflamed airway, the responses against the virus may be impaired or aberrant, causing sustained inflammation and erroneous infiltration, resulting in the exacerbation of their symptoms Mallia and Johnston, 2006; Dougherty and Fahy, 2009; Busse et al., 2010; Britto et al., 2017; Linden et al., 2019 . This is usually further compounded by the increased susceptibility of chronic airway inflammatory disease patients toward viral respiratory infections, thereby increasing the frequency of exacerbation as a whole Dougherty and Fahy, 2009; Busse et al., 2010; Linden et al., 2019 . Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity.", "Furthermore, due to the different replication cycles and response against the myriad of respiratory viruses, each respiratory virus may also contribute to exacerbations via different mechanisms that may alter their severity. Hence, this review will focus on compiling and collating the current known mechanisms of viral-induced exacerbation of chronic airway inflammatory diseases; as well as linking the different viral infection pathogenesis to elucidate other potential ways the infection can exacerbate the disease. The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation.", "The review will serve to provide further understanding of viral induced exacerbation to identify potential pathways and pathogenesis mechanisms that may be targeted as supplementary care for management and prevention of exacerbation. Such an approach may be clinically significant due to the current scarcity of antiviral drugs for the management of viral-induced exacerbations. This will improve the quality of life of patients with chronic airway inflammatory diseases.", "This will improve the quality of life of patients with chronic airway inflammatory diseases. Once the link between viral infection and acute exacerbations of chronic airway inflammatory disease was established, there have been many reports on the mechanisms underlying the exacerbation induced by respiratory viral infection. Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection.", "Upon infecting the host, viruses evoke an inflammatory response as a means of counteracting the infection. Generally, infected airway epithelial cells release type I IFNα/β and type III IFNλ interferons, cytokines and chemokines such as IL-6, IL-8, IL-12, RANTES, macrophage inflammatory protein 1α MIP-1α and monocyte chemotactic protein 1 MCP-1 Wark and Gibson, 2006; Matsukura et al., 2013 . These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 .", "These, in turn, enable infiltration of innate immune cells and of professional antigen presenting cells APCs that will then in turn release specific mediators to facilitate viral targeting and clearance, including type II interferon IFNγ , IL-2, IL-4, IL-5, IL-9, and IL-12 Wark and Gibson, 2006; Singh et al., 2010; Braciale et al., 2012 . These factors heighten local inflammation and the infiltration of granulocytes, T-cells and B-cells Wark and Gibson, 2006; Braciale et al., 2012 . The increased inflammation, in turn, worsens the symptoms of airway diseases.", "The increased inflammation, in turn, worsens the symptoms of airway diseases. Additionally, in patients with asthma and patients with CRS with nasal polyp CRSwNP , viral infections such as RV and RSV promote a Type 2-biased immune response Becker, 2006; Jackson et al., 2014; Jurak et al., 2018 . This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 .", "This amplifies the basal type 2 inflammation resulting in a greater release of IL-4, IL-5, IL-13, RANTES and eotaxin and a further increase in eosinophilia, a key pathological driver of asthma and CRSwNP Wark and Gibson, 2006; Singh et al., 2010; Chung et al., 2015; Dunican and Fahy, 2015 . Increased eosinophilia, in turn, worsens the classical symptoms of disease and may further lead to life-threatening conditions due to breathing difficulties. On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 .", "On the other hand, patients with COPD and patients with CRS without nasal polyp CRSsNP are more neutrophilic in nature due to the expression of neutrophil chemoattractants such as CXCL9, CXCL10, and CXCL11 Cukic et al., 2012; Brightling and Greening, 2019 . The pathology of these airway diseases is characterized by airway remodeling due to the presence of remodeling factors such as matrix metalloproteinases MMPs released from infiltrating neutrophils . .", ". Viral infections in such conditions will then cause increase neutrophilic activation; worsening the symptoms and airway remodeling in the airway thereby exacerbating COPD, CRSsNP and even CRSwNP in certain cases Wang et al., 2009; Tacon et al., 2010; Linden et al., 2019 . An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 .", "An epithelial-centric alarmin pathway around IL-25, IL-33 and thymic stromal lymphopoietin TSLP , and their interaction with group 2 innate lymphoid cells ILC2 has also recently been identified Nagarkar et al., 2012; Hong et al., 2018; Allinne et al., 2019 . IL-25, IL-33 and TSLP are type 2 inflammatory cytokines expressed by the epithelial cells upon injury to the epithelial barrier Gabryelska et al., 2019; Roan et al., 2019 . ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 .", "ILC2s are a group of lymphoid cells lacking both B and T cell receptors but play a crucial role in secreting type 2 cytokines to perpetuate type 2 inflammation when activated Scanlon and McKenzie, 2012; Li and Hendriks, 2013 . In the event of viral infection, cell death and injury to the epithelial barrier will also induce the expression of IL-25, IL-33 and TSLP, with heighten expression in an inflamed airway Allakhverdi et al., 2007; Goldsmith et al., 2012; Byers et al., 2013; Shaw et al., 2013; Beale et al., 2014; Jackson et al., 2014; Uller and Persson, 2018; Ravanetti et al., 2019 . These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation .", "These 3 cytokines then work in concert to activate ILC2s to further secrete type 2 cytokines IL-4, IL-5, and IL-13 which further aggravate the type 2 inflammation in the airway causing acute exacerbation . . In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation .", "In the case of COPD, increased ILC2 activation, which retain the capability of differentiating to ILC1, may also further augment the neutrophilic response and further aggravate the exacerbation . . Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways .", "Interestingly, these factors are not released to any great extent and do not activate an ILC2 response during viral infection in healthy individuals Yan et al., 2016; Tan et al., 2018a ; despite augmenting a type 2 exacerbation in chronically inflamed airways . . These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 .", ". These classical mechanisms of viral induced acute exacerbations are summarized in Figure 1 . As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases.", "As integration of the virology, microbiology and immunology of viral infection becomes more interlinked, additional factors and FIGURE 1 | Current understanding of viral induced exacerbation of chronic airway inflammatory diseases. Upon virus infection in the airway, antiviral state will be activated to clear the invading pathogen from the airway. Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance.", "Immune response and injury factors released from the infected epithelium normally would induce a rapid type 1 immunity that facilitates viral clearance. However, in the inflamed airway, the cytokines and chemokines released instead augmented the inflammation present in the chronically inflamed airway, strengthening the neutrophilic infiltration in COPD airway, and eosinophilic infiltration in the asthmatic airway. The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway.", "The effect is also further compounded by the participation of Th1 and ILC1 cells in the COPD airway; and Th2 and ILC2 cells in the asthmatic airway. Frontiers in Cell and Developmental Biology | mechanisms have been implicated in acute exacerbations during and after viral infection . . Murray et al. .", ". Murray et al. . has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway.", "has underlined the synergistic effect of viral infection with other sensitizing agents in causing more severe acute exacerbations in the airway. This is especially true when not all exacerbation events occurred during the viral infection but may also occur well after viral clearance Kim et al., 2008; Stolz et al., 2019 in particular the late onset of a bacterial infection Singanayagam et al., 2018 Singanayagam et al., , 2019a . In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections.", "In addition, viruses do not need to directly infect the lower airway to cause an acute exacerbation, as the nasal epithelium remains the primary site of most infections. Moreover, not all viral infections of the airway will lead to acute exacerbations, suggesting a more complex interplay between the virus and upper airway epithelium which synergize with the local airway environment in line with the \"united airway\" hypothesis . .", ". On the other hand, viral infections or their components persist in patients with chronic airway inflammatory disease Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Hence, their presence may further alter the local environment and contribute to current and future exacerbations.", "Hence, their presence may further alter the local environment and contribute to current and future exacerbations. Future studies should be performed using metagenomics in addition to PCR analysis to determine the contribution of the microbiome and mycobiome to viral infections. In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases.", "In this review, we highlight recent data regarding viral interactions with the airway epithelium that could also contribute to, or further aggravate, acute exacerbations of chronic airway inflammatory diseases. Patients with chronic airway inflammatory diseases have impaired or reduced ability of viral clearance Hammond et al., 2015; McKendry et al., 2016; Akbarshahi et al., 2018; Gill et al., 2018; Wang et al., 2018; Singanayagam et al., 2019b . Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 .", "Their impairment stems from a type 2-skewed inflammatory response which deprives the airway of important type 1 responsive CD8 cells that are responsible for the complete clearance of virusinfected cells Becker, 2006; McKendry et al., 2016 . This is especially evident in weak type 1 inflammation-inducing viruses such as RV and RSV Kling et al., 2005; Wood et al., 2011; Ravi et al., 2019 . Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 .", "Additionally, there are also evidence of reduced type I IFNβ and III IFNλ interferon production due to type 2-skewed inflammation, which contributes to imperfect clearance of the virus resulting in persistence of viral components, or the live virus in the airway epithelium Contoli et al., 2006; Hwang et al., 2019; Wark, 2019 . Due to the viral components remaining in the airway, antiviral genes such as type I interferons, inflammasome activating factors and cytokines remained activated resulting in prolong airway inflammation Wood et al., 2011; Essaidi-Laziosi et al., 2018 . These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms.", "These factors enhance granulocyte infiltration thus prolonging the exacerbation symptoms. Such persistent inflammation may also be found within DNA viruses such as AdV, hCMV and HSV, whose infections generally persist longer Imperiale and Jiang, 2015 , further contributing to chronic activation of inflammation when they infect the airway Yang et al., 2008; Morimoto et al., 2009; Imperiale and Jiang, 2015; Lan et al., 2016; Tan et al., 2016; Kowalski et al., 2017 . With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 .", "With that note, human papilloma virus HPV , a DNA virus highly associated with head and neck cancers and respiratory papillomatosis, is also linked with the chronic inflammation that precedes the malignancies de Visser et al., 2005; Gillison et al., 2012; Bonomi et al., 2014; Fernandes et al., 2015 . Therefore, the role of HPV infection in causing chronic inflammation in the airway and their association to exacerbations of chronic airway inflammatory diseases, which is scarcely explored, should be investigated in the future. Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 .", "Furthermore, viral persistence which lead to continuous expression of antiviral genes may also lead to the development of steroid resistance, which is seen with RV, RSV, and PIV infection Chi et al., 2011; Ford et al., 2013; Papi et al., 2013 . The use of steroid to suppress the inflammation may also cause the virus to linger longer in the airway due to the lack of antiviral clearance Kim et al., 2008; Hammond et al., 2015; Hewitt et al., 2016; McKendry et al., 2016; Singanayagam et al., 2019b . The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection.", "The concomitant development of steroid resistance together with recurring or prolong viral infection thus added considerable burden to the management of acute exacerbation, which should be the future focus of research to resolve the dual complications arising from viral infection. On the other end of the spectrum, viruses that induce strong type 1 inflammation and cell death such as IFV Yan et al., 2016; Guibas et al., 2018 and certain CoV including the recently emerged COVID-19 virus Tao et al., 2013; Yue et al., 2018; Zhu et al., 2020 , may not cause prolonged inflammation due to strong induction of antiviral clearance. These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 .", "These infections, however, cause massive damage and cell death to the epithelial barrier, so much so that areas of the epithelium may be completely absent post infection Yan et al., 2016; Tan et al., 2019 . Factors such as RANTES and CXCL10, which recruit immune cells to induce apoptosis, are strongly induced from IFV infected epithelium Ampomah et al., 2018; Tan et al., 2019 . Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium .", "Additionally, necroptotic factors such as RIP3 further compounds the cell deaths in IFV infected epithelium . The massive cell death induced may result in worsening of the acute exacerbation due to the release of their cellular content into the airway, further evoking an inflammatory response in the airway . .", ". Moreover, the destruction of the epithelial barrier may cause further contact with other pathogens and allergens in the airway which may then prolong exacerbations or results in new exacerbations. Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors .", "Epithelial destruction may also promote further epithelial remodeling during its regeneration as viral infection induces the expression of remodeling genes such as MMPs and growth factors . Infections that cause massive destruction of the epithelium, such as IFV, usually result in severe acute exacerbations with non-classical symptoms of chronic airway inflammatory diseases. Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation.", "Fortunately, annual vaccines are available to prevent IFV infections Vasileiou et al., 2017; Zheng et al., 2018 ; and it is recommended that patients with chronic airway inflammatory disease receive their annual influenza vaccination as the best means to prevent severe IFV induced exacerbation. Another mechanism that viral infections may use to drive acute exacerbations is the induction of vasodilation or tight junction opening factors which may increase the rate of infiltration. Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration.", "Infection with a multitude of respiratory viruses causes disruption of tight junctions with the resulting increased rate of viral infiltration. This also increases the chances of allergens coming into contact with airway immune cells. For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 .", "For example, IFV infection was found to induce oncostatin M OSM which causes tight junction opening Pothoven et al., 2015; Tian et al., 2018 . Similarly, RV and RSV infections usually cause tight junction opening which may also increase the infiltration rate of eosinophils and thus worsening of the classical symptoms of chronic airway inflammatory diseases Sajjan et al., 2008; Kast et al., 2017; Kim et al., 2018 . In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 .", "In addition, the expression of vasodilating factors and fluid homeostatic factors such as angiopoietin-like 4 ANGPTL4 and bactericidal/permeabilityincreasing fold-containing family member A1 BPIFA1 are also associated with viral infections and pneumonia development, which may worsen inflammation in the lower airway Akram et al., 2018 . These factors may serve as targets to prevent viral-induced exacerbations during the management of acute exacerbation of chronic airway inflammatory diseases. Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome.", "Another recent area of interest is the relationship between asthma and COPD exacerbations and their association with the airway microbiome. The development of chronic airway inflammatory diseases is usually linked to specific bacterial species in the microbiome which may thrive in the inflamed airway environment . .", ". In the event of a viral infection such as RV infection, the effect induced by the virus may destabilize the equilibrium of the microbiome present Molyneaux et al., 2013; Kloepfer et al., 2014; Kloepfer et al., 2017; Jubinville et al., 2018; van Rijn et al., 2019 . In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 .", "In addition, viral infection may disrupt biofilm colonies in the upper airway e.g., Streptococcus pneumoniae microbiome to be release into the lower airway and worsening the inflammation Marks et al., 2013; Chao et al., 2014 . Moreover, a viral infection may also alter the nutrient profile in the airway through release of previously inaccessible nutrients that will alter bacterial growth Siegel et al., 2014; Mallia et al., 2018 . Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 .", "Furthermore, the destabilization is further compounded by impaired bacterial immune response, either from direct viral influences, or use of corticosteroids to suppress the exacerbation symptoms Singanayagam et al., 2018 Singanayagam et al., , 2019a Wang et al., 2018; Finney et al., 2019 . All these may gradually lead to more far reaching effect when normal flora is replaced with opportunistic pathogens, altering the inflammatory profiles . .", ". These changes may in turn result in more severe and frequent acute exacerbations due to the interplay between virus and pathogenic bacteria in exacerbating chronic airway inflammatory diseases Wark et al., 2013; Singanayagam et al., 2018 . To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome .", "To counteract these effects, microbiome-based therapies are in their infancy but have shown efficacy in the treatments of irritable bowel syndrome by restoring the intestinal microbiome . . Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection.", "Further research can be done similarly for the airway microbiome to be able to restore the microbiome following disruption by a viral infection. Viral infections can cause the disruption of mucociliary function, an important component of the epithelial barrier. Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases.", "Ciliary proteins FIGURE 2 | Changes in the upper airway epithelium contributing to viral exacerbation in chronic airway inflammatory diseases. The upper airway epithelium is the primary contact/infection site of most respiratory viruses. Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations.", "Therefore, its infection by respiratory viruses may have far reaching consequences in augmenting and synergizing current and future acute exacerbations. The destruction of epithelial barrier, mucociliary function and cell death of the epithelial cells serves to increase contact between environmental triggers with the lower airway and resident immune cells. The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations.", "The opening of tight junction increasing the leakiness further augments the inflammation and exacerbations. In addition, viral infections are usually accompanied with oxidative stress which will further increase the local inflammation in the airway. The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation.", "The dysregulation of inflammation can be further compounded by modulation of miRNAs and epigenetic modification such as DNA methylation and histone modifications that promote dysregulation in inflammation. Finally, the change in the local airway environment and inflammation promotes growth of pathogenic bacteria that may replace the airway microbiome. Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection.", "Furthermore, the inflammatory environment may also disperse upper airway commensals into the lower airway, further causing inflammation and alteration of the lower airway environment, resulting in prolong exacerbation episodes following viral infection. Viral specific trait contributing to exacerbation mechanism with literature evidence Oxidative stress ROS production RV, RSV, IFV, HSV As RV, RSV, and IFV were the most frequently studied viruses in chronic airway inflammatory diseases, most of the viruses listed are predominantly these viruses. However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations .", "However, the mechanisms stated here may also be applicable to other viruses but may not be listed as they were not implicated in the context of chronic airway inflammatory diseases exacerbation see text for abbreviations . that aid in the proper function of the motile cilia in the airways are aberrantly expressed in ciliated airway epithelial cells which are the major target for RV infection . .", ". Such form of secondary cilia dyskinesia appears to be present with chronic inflammations in the airway, but the exact mechanisms are still unknown Peng et al., , 2019 Qiu et al., 2018 . Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b .", "Nevertheless, it was found that in viral infection such as IFV, there can be a change in the metabolism of the cells as well as alteration in the ciliary gene expression, mostly in the form of down-regulation of the genes such as dynein axonemal heavy chain 5 DNAH5 and multiciliate differentiation And DNA synthesis associated cell cycle protein MCIDAS Tan et al., 2018b . The recently emerged Wuhan CoV was also found to reduce ciliary beating in infected airway epithelial cell model . .", ". Furthermore, viral infections such as RSV was shown to directly destroy the cilia of the ciliated cells and almost all respiratory viruses infect the ciliated cells Jumat et al., 2015; Yan et al., 2016; Tan et al., 2018a . In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation .", "In addition, mucus overproduction may also disrupt the equilibrium of the mucociliary function following viral infection, resulting in symptoms of acute exacerbation . . Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage.", "Hence, the disruption of the ciliary movement during viral infection may cause more foreign material and allergen to enter the airway, aggravating the symptoms of acute exacerbation and making it more difficult to manage. The mechanism of the occurrence of secondary cilia dyskinesia can also therefore be explored as a means to limit the effects of viral induced acute exacerbation. MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases .", "MicroRNAs miRNAs are short non-coding RNAs involved in post-transcriptional modulation of biological processes, and implicated in a number of diseases . . miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 .", "miRNAs are found to be induced by viral infections and may play a role in the modulation of antiviral responses and inflammation Gutierrez et al., 2016; Deng et al., 2017; Feng et al., 2018 . In the case of chronic airway inflammatory diseases, circulating miRNA changes were found to be linked to exacerbation of the diseases . .", ". Therefore, it is likely that such miRNA changes originated from the infected epithelium and responding immune cells, which may serve to further dysregulate airway inflammation leading to exacerbations. Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids .", "Both IFV and RSV infections has been shown to increase miR-21 and augmented inflammation in experimental murine asthma models, which is reversed with a combination treatment of anti-miR-21 and corticosteroids . . IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 .", "IFV infection is also shown to increase miR-125a and b, and miR-132 in COPD epithelium which inhibits A20 and MAVS; and p300 and IRF3, respectively, resulting in increased susceptibility to viral infections Hsu et al., 2016 Hsu et al., , 2017 . Conversely, miR-22 was shown to be suppressed in asthmatic epithelium in IFV infection which lead to aberrant epithelial response, contributing to exacerbations . .", ". Other than these direct evidence of miRNA changes in contributing to exacerbations, an increased number of miRNAs and other non-coding RNAs responsible for immune modulation are found to be altered following viral infections Globinska et al., 2014; Feng et al., 2018; Hasegawa et al., 2018 . Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases.", "Hence non-coding RNAs also presents as targets to modulate viral induced airway changes as a means of managing exacerbation of chronic airway inflammatory diseases. Other than miRNA modulation, other epigenetic modification such as DNA methylation may also play a role in exacerbation of chronic airway inflammatory diseases. Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 .", "Recent epigenetic studies have indicated the association of epigenetic modification and chronic airway inflammatory diseases, and that the nasal methylome was shown to be a sensitive marker for airway inflammatory changes Cardenas et al., 2019; Gomez, 2019 . At the same time, it was also shown that viral infections such as RV and RSV alters DNA methylation and histone modifications in the airway epithelium which may alter inflammatory responses, driving chronic airway inflammatory diseases and exacerbations McErlean et al., 2014; Pech et al., 2018; Caixia et al., 2019 . In addition, Spalluto et al.", "In addition, Spalluto et al. . also showed that antiviral factors such as IFNγ epigenetically modifies the viral resistance of epithelial cells. Hence, this may indicate that infections such as RV and RSV that weakly induce antiviral responses may result in an altered inflammatory state contributing to further viral persistence and exacerbation of chronic airway inflammatory diseases . .", ". Finally, viral infection can result in enhanced production of reactive oxygen species ROS , oxidative stress and mitochondrial dysfunction in the airway epithelium Kim et al., 2018; Mishra et al., 2018; Wang et al., 2018 . The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 .", "The airway epithelium of patients with chronic airway inflammatory diseases are usually under a state of constant oxidative stress which sustains the inflammation in the airway Barnes, 2017; van der Vliet et al., 2018 . Viral infections of the respiratory epithelium by viruses such as IFV, RV, RSV and HSV may trigger the further production of ROS as an antiviral mechanism Aizawa et al., 2018; Wang et al., 2018 . Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region.", "Moreover, infiltrating cells in response to the infection such as neutrophils will also trigger respiratory burst as a means of increasing the ROS in the infected region. The increased ROS and oxidative stress in the local environment may serve as a trigger to promote inflammation thereby aggravating the inflammation in the airway . .", ". A summary of potential exacerbation mechanisms and the associated viruses is shown in Figure 2 and Table 1 . While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients.", "While the mechanisms underlying the development and acute exacerbation of chronic airway inflammatory disease is extensively studied for ways to manage and control the disease, a viral infection does more than just causing an acute exacerbation in these patients. A viral-induced acute exacerbation not only induced and worsens the symptoms of the disease, but also may alter the management of the disease or confer resistance toward treatments that worked before. Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms.", "Hence, appreciation of the mechanisms of viral-induced acute exacerbations is of clinical significance to devise strategies to correct viral induce changes that may worsen chronic airway inflammatory disease symptoms. Further studies in natural exacerbations and in viral-challenge models using RNA-sequencing RNA-seq or single cell RNA-seq on a range of time-points may provide important information regarding viral pathogenesis and changes induced within the airway of chronic airway inflammatory disease patients to identify novel targets and pathway for improved management of the disease. Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a .", "Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway Yan et al., 2016; Boda et al., 2018; Tan et al., 2018a . Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation Shin, 2016; Gubernatorova et al., 2019; Tanner and Single, 2019 . Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 .", "Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition Ito et al., 2019; Li and Di Santo, 2019 . For milder viruses, controlled in vivo human infections can be performed for the best mode of verification of the associations of the virus with the proposed mechanism of viral induced acute exacerbations . With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations.", "With the advent of suitable diseased models, the verification of the mechanisms will then provide the necessary continuation of improving the management of viral induced acute exacerbations. In conclusion, viral-induced acute exacerbation of chronic airway inflammatory disease is a significant health and economic burden that needs to be addressed urgently. In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease.", "In view of the scarcity of antiviral-based preventative measures available for only a few viruses and vaccines that are only available for IFV infections, more alternative measures should be explored to improve the management of the disease. Alternative measures targeting novel viral-induced acute exacerbation mechanisms, especially in the upper airway, can serve as supplementary treatments of the currently available management strategies to augment their efficacy. New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms.", "New models including primary human bronchial or nasal epithelial cell cultures, organoids or precision cut lung slices from patients with airways disease rather than healthy subjects can be utilized to define exacerbation mechanisms. These mechanisms can then be validated in small clinical trials in patients with asthma or COPD. Having multiple means of treatment may also reduce the problems that arise from resistance development toward a specific treatment." ]