Pulmonary fibrosis after COVID-19 is characterized by airway abnormalities and elevated club cell secretory protein-16

Prior studies testing biomarkers of residual lung abnormalities after COVID-19 are limited by sampling within the first year after acute COVID-19 illness and lack of external validation of findings. In three independent, international, racially and ethnically diverse prospective cohorts of survivors of moderate to critical COVID-19, we systematically tested 18 circulating biomarkers of inflammation, aging, endothelial activation, pulmonary epithelial function, fibrosis, and fibrinolysis. We found that only higher club-cell secretory protein-16 (CC16) levels are consistently associated with persistent fibrotic lung abnormalities in cross-sectional and longitudinal analyses for up to 3 years after acute COVID-19. Histopathological and single-cell RNA sequencing analyses of transbronchial biopsies of fibrotic lung abnormalities in COVID-19 survivors sampled between 3 and 4 years after acute illness and of COVID-19 lung explants suggest that circulating CC16 reflects underlying deranged pulmonary epithelial progenitor proliferation and anomalous CC16/MUC5B-related pro-fibrotic signaling in the distal airways. CC16 should be investigated further as a potential blood biomarker that may facilitate screening of COVID-19 survivors for pulmonary fibrosis and its progression.