text: Immuno fibrotic drivers of impaired lung function in post acute sequelae of SARS CoV 2 infection PASC Subjects recovering from COVID 19 frequently experience persistent respiratory ailments however little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID 19 severity We performed a prospective cohort study of subjects with persistent symptoms after acute COVID 19 collecting clinical data pulmonary function tests and plasma samples used for multiplex profiling of inflammatory metabolic angiogenic and fibrotic factors Sixty one subjects were enrolled across two academic medical centers at a median of 9 weeks interquartile range 6 10 after COVID 19 illness n 13 subjects 21 mild non hospitalized n 30 49 hospitalized non critical and n 18 subjects 30 hospitalized intensive care ICU Fifty three subjects 85 had lingering symptoms most commonly dyspnea 69 and cough 58 Forced vital capacity FVC forced expiratory volume in 1 second FEV1 and diffusing capacity for carbon monoxide DLCO declined as COVID 19 severity increased P 0 05 but did not correlate with respiratory symptoms Partial least squares discriminant analysis of plasma biomarker profiles clustered subjects by past COVID 19 severity Lipocalin 2 LCN2 matrix metalloproteinase 7 MMP 7 and hepatocyte growth factor HGF identified by the model were significantly higher in the ICU group P 0 05 and inversely correlated with FVC and DLCO P 0 05 and were confirmed in a separate validation cohort n 53 Subjective respiratory symptoms are common after acute COVID 19 illness but do not correlate with COVID 19 severity or pulmonary function Host response profiles reflecting neutrophil activation LCN2 fibrosis signaling MMP 7 and alveolar repair HGF track with lung impairment and may be novel therapeutic or prognostic targets The study was funded in part by the NHLBI K08HL130557 to BDK and R01HL142818 to HJC the DeLuca Foundation Award AP a donation from Jack Levin to the Benign Hematology Program at Yale and Divisional Departmental funds from Duke University 