text: Incomplete Systemic Recovery and Metabolic Phenoreversion in Post Acute Phase Nonhospitalized COVID 19 Patients Implications for Assessment of Post Acute COVID 19 Syndrome We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized COVID 19 patients and the possible biochemical sequelae of Post Acute COVID 19 Syndrome colloquially known as long COVID Blood samples were taken from patients ca 3 months after acute COVID 19 infection with further assessment of symptoms at 6 months Some 57 of the patients had one or more persistent symptoms including respiratory related symptoms like cough dyspnea and rhinorrhea or other nonrespiratory symptoms including chronic fatigue anosmia myalgia or joint pain Plasma samples were quantitatively analyzed for lipoproteins glycoproteins amino acids biogenic amines and tryptophan pathway intermediates using Nuclear Magnetic Resonance NMR spectroscopy and mass spectrometry Metabolic data for the follow up patients i n i 27 were compared with controls i n i 41 and hospitalized severe acute respiratory syndrome SARS CoV 2 positive patients i n i 18 with multiple time points Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID 19 biomarker signatures Several parameters were persistently perturbed e g elevated taurine i p i 3 6 10 sup 3 sup versus controls and reduced glutamine glutamate ratio i p i 6 95 10 sup 8 sup versus controls indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function Some parameters showed near complete normalization e g the plasma apolipoprotein B100 A1 ratio was similar to that of healthy controls but significantly lower i p i 4 2 10 sup 3 sup than post acute COVID 19 patients reflecting partial reversion of the metabolic phenotype phenoreversion toward the healthy metabolic state Plasma neopterin was normalized in all follow up patients indicative of a reduction in the adaptive immune activity that has been previously detected in active SARS CoV 2 infection Other systemic inflammatory biomarkers such as GlycA and the kynurenine tryptophan ratio remained elevated in some but not all patients Correlation analysis principal component analysis PCA and orthogonal partial least squares discriminant analysis O PLS DA showed that the follow up patients were as a group metabolically distinct from controls and partially comapped with the acute phase patients Significant systematic metabolic differences between asymptomatic and symptomatic follow up patients were also observed for multiple metabolites The overall metabolic variance of the symptomatic patients was significantly greater than that of nonsymptomatic patients for multiple parameters χ sup 2 sup i p i 0 014 Thus asymptomatic follow up patients including those with post acute COVID 19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post acute COVID 19 patients 