question: COVID-19 is a multiorgan disease that most prominently causes respiratory failure and the acute respiratory distress syndrome (ARDS). Epidemiologic studies of patients with COVID-19 have shown a high percentage of hospitalized patients requiring intensive care and prolonged invasive mechanical ventilation and high mortality. The cellular mechanisms that underlie prolonged ventilator dependence and high mortality in these patients remain unknown. Previous studies in alveolar epithelial regeneration have identified the presence and a possible pathogenic role of a persistent transitional cell state that cuboidal type 2 cells (AEC2s) adopt during differentiation into squamous type 1 cells (AEC1s). This transitional state has a unique gene expression signature that includes strong expression or keratin 8 (Krt8). We hypothesized that ARDS secondary to COVID-19 was associated with the persistence of the transitional state of alveolar regeneration, perhaps contributing to prolonged ventilator dependence and mortality. Institutional review board approval was obtained for relevant clinical data. Briefly, the patients included in this study developed progressively worsening ARDS despite lung protective ventilation and adjunctive therapies, with progressive diffuse alveolar infiltrates on serial imaging. All patients died within two weeks of hospitalization, and all had persistent hypoxemia despite maximally tolerable ventilator support near the end of life. Lung tissue from autopsy specimens from these patients was utilized for immunofluorescence, hematoxylin and eosin, and trichrome staining. Histology was consistent with diffuse alveolar damage. Staining revealed extensive damage to AEC1s (Figure 1, stained for HTI-56) and AEC2s (not shown) and abundant Krt8hi transitional cells (Figure 1) in lung tissue from COVID-19 patients (Figure 1) without significant fibrosis. Our findings establis h the presence of Krt8hi transitional cells in conjunction with extensive alveolar epithelial damage and failure to regenerate AEC1s. We speculate that prolonged barrier dysfunction from dysregulated alveolar repair, perhaps mediated by a failure of Krt8hi transitional cells to differentiate into mature AEC1s, contributes to ventilator dependent respiratory failure and mortality. Though prior studies have suggested a role of persistent Krt8hi transitional cells in fibrosis, our findings suggest that prevalence of Krt8hi transitional cells alone is not sufficient to cause fibrosis, suggesting that that the extensive epithelial damage observed in COVID-19 ARDS is potentially reversible. We conclude that in severe COVID-19 ARDS, alveolar regeneration is incomplete, characterized by persistence of the Krt8hi transitional state but that differentiation of these cells into mature AEC1s resulting in barrier restoration and clinical recovery may still be possible.