Respiratory viruses, including SARS-CoV-2, can trigger chronic lung disease that persists and even progresses after expected clearance of infectious virus. To gain an understanding of this process, we examined a series of consecutive fatal cases of Covid-19 that came to autopsy at 27-51 d after hospital admission. In each patient, we identify a stereotyped bronchiolar-alveolar pattern of lung remodeling with basal epithelial cell hyperplasia and mucinous differentiation. Remodeling regions also feature macrophage infiltration and apoptosis and a marked depletion of alveolar type 1 and 2 epithelial cells. This entire pattern closely resembles findings from an experimental model of post-viral lung disease that requires basal-epithelial stem cell growth, immune activation, and differentiation. The present results thereby provide evidence of possible basal epithelial cell reprogramming in long-term Covid-19 as well and thereby a pathway for explaining and correcting lung dysfunction in this type of disease.

MJH is Founder of NuPeak Therapeutics and a scientific advisor for Lonza Bend. DEB is a consultant for AstraZeneca. The other authors have no potential financial conflicts of interest to declare.

This work was supported by grants from the National Institutes of Health (National Heart, Lung, and Blood Institute R35-HL145242, National Institute of Allergy and Infectious Diseases R01-AI130591), Department of Defense (PR190726 and PR211069), and the Harrington Discovery Institute, Cystic Fibrosis Foundation, Bebermeyer Fund, Hardy Trust, and Schaefer Fund.

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