Persistent alveolar type 2 dysfunction and lung structural derangement in post-acute COVID-19

Abstract

SARS-CoV-2 infection can manifest as a wide range of respiratory and systemic symptoms well after the acute phase of infection in over 50% of patients. Key questions remain on the long-term effects of infection on tissue pathology in recovered COVID-19 patients. To address these questions we performed multiplexed imaging of post-mortem lung tissue from 12 individuals who died post-acute COVID-19 (PC) and compare them to lung tissue from patients who died during the acute phase of COVID-19, or patients who died with idiopathic pulmonary fibrosis (IPF), and otherwise healthy lung tissue. We find evidence of viral presence in the lung up to 359 days after the acute phase of disease, including in patients with negative nasopharyngeal swab tests. The lung of PC patients are characterized by the accumulation of senescent alveolar type 2 cells, fibrosis with hypervascularization of peribronchial areas and alveolar septa, as the most pronounced pathophysiological features. At the cellular level, lung disease of PC patients, while distinct, shares pathological features with the chronic pulmonary disease of IPF. which may help rationalize interventions for PC patients. Altogether, this study provides an important foundation for the understanding of the long-term effects of SARS-CoV-2 pulmonary infection at the microanatomical, cellular, and molecular level.

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

“…Consistent with the observed fibrotic sequelae, we found reduced levels of AT1 and AT2 cells in PASC-PF lungs compared to controls, suggesting a persistent defect in alveolar regeneration (Fig. 1b,c) (39). We also observed chronic persistence of ectopic Krt5 + basal cells and Krt8 hi transitional cells in PASC-PF lungs compared to controls, which is concordant with recent reports (5, 8, 30, 40) (Fig.…”

“…1f, Extended data Fig. 2a) (38). We also observed chronic persistence of ectopic Krt5 + pods, Krt8 hi transitional cells, and Krt5 - Krt17 + aberrant basaloid cells in PASC-PF lungs compared to controls, which is concordant with recent reports (5, 8, 32, 39) (Fig.…”

“…Recent efforts have revealed several histopathological features conserved across various cohorts of respiratory PASC and PASC-PF patients including the prolonged reduction in alveolar epithelial cells (39), maintenance of Krt8 hi and Krt5 + dysplastic progenitors (5,8), and the persistence of various immune cell populations in the lungs (9,10,53). Although immunederived cues have recently been shown to influence lung repair (11,21,48,50,54), their exact interactions, if any, with the alveolar epithelium and role in post-viral fibrosis remain unexplored.…”