Introduction: Subjects recovering from COVID-19 frequently experience persistent respiratory ailments which are key elements of post-acute sequelae of SARS-CoV-2 infection (PASC); 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. Methods: 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.Results: 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/nonhospitalized, 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). Conclusions: 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.

Subjects recovering from COVID-19 frequently experience persistent respiratory ailments; however, little is known about the underlying biology that directs lung recovery and its relation to COVID-19 severity. We performed a cohort study of subjects with lingering symptoms after COVID-19, collecting clinical data, pulmonary function tests, and plasma for multiplex biomarker profiling. Sixty-one subjects were enrolled across two academic medical centers at a median of 9 weeks post-COVID-19: n=13 (21%) mild/non-hospitalized, n=30 (49%) hospitalized/non-critical, and n=18 (30%) hospitalized/ICU. Dyspnea (69%) and cough (58%) were common. Pulmonary function at follow-up declined as acute COVID-19 severity increased (P<0.05), but did not correlate with symptoms. Partial least-squares discriminant analysis of biomarkers clustered subjects by COVID-19 severity. Lipocalin 2 (LCN2), matrix metalloproteinase-7 (MMP-7), and hepatocyte growth factor (HGF) were significantly higher in ICU subjects (P<0.05), and inversely correlated with pulmonary function (P<0.05). These host response profiles reflecting neutrophil activation, fibrosis signaling, and alveolar repair, respectively, may be novel therapeutic or prognostic targets in post-COVID-19 syndrome.SummaryCOVID-19 “long-haulers” display impaired lung function and a lung recovery host response that is proportionate to degree of acute lung injury. Novel biomarkers of inflammation, fibrosis, and alveolar repair may reflect underlying biological drivers of post-COVID-19 syndrome.

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