This series of lung autopsy samples from patients with fatal SARS-CoV-2 infection showed a wide range of aberrant pulmonary responses to infection that were associated with viral load, immune response, and duration of clinical illness before death. Pulmonary pathologic changes over a wide range of illness durations (SOTDs ranging from 3 to 47 days) were investigated. Although pathologic changes likely occurred asynchronously throughout the lung, and although each case examined resulted in a fatal outcome regardless of SOTD duration, these observations nevertheless suggested a temporal framework for disease progression, that is, a natural history and pathogenesis of SARS-CoV-2 infection (fig. S17).
Pathological observations indicated that both direct virus-induced cytopathic effects and host inflammatory and immune responses led to early pulmonary epithelial and endothelial injury, alveolar-capillary barrier dysfunction, impaired lung tissue repair processes, and widespread vascular thrombosis with reduced fibrinolysis. Furthermore, in cases with a longer disease duration, disease progression led to excessive pulmonary fibrosis, loss of alveoli, and vascular remodeling. Our study also demonstrated epithelial and endothelial cell senescence in the pathophysiology of COVID-19, consistent with increased susceptibility and severity of COVID-19 in the elderly and comorbid risk populations.
There are certain limitations to our study. Whereas the present case series allowed for the examination of lung tissue from COVID-19 patients with short, intermediate, or long clinical illness duration, the overall number of patients was small. Larger autopsy studies will be needed to specifically examine mitigating factors including varying patient demographics, comorbidities, and in-hospital interventions (e.g., mechanical ventilatory support). Another potential concern is related to lung tissue sampling, and specifically, whether the available lung specimens used for imaging and transcriptomic analyses were representative of the whole lung. Finally, as all cases in this study were fatal, it is unknown to what extent these pathological processes occur in mild to moderate or hospitalized, non-fatal COVID-19 cases, or in cases with long-term sequelae post-SARS-CoV-2 infection.
In summary, the present study provides insight into the pathological, immunological, and host genetic correlates of progressive pulmonary failure and impaired tissue repair in fatal COVID-19. The data presented here highlight key scientific links between these processes and common comorbidities including age, diabetes, and obesity that may help to define important determinants of disease severity and recovery. A more complete understanding of the specific interplay between these pulmonary responses and cellular senescence-driven risk factors may prove critical in the development of relevant disease markers and urgently needed therapeutics.
We thank David M. Morens for helpful discussions.
Funding: This project (1ZIAAI001271-01) was funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the NIH (to JKT), by Intramural funding from the Center for Biologics Evaluation and Research, FDA (to FD), an early postdoctoral mobility fellowship (P2BSP3_188158) awarded by the Swiss National Science Foundation (to SG), and the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (to KS). This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.
Author contributions: FD, KAW, JCK, JKT conceived and designed experiments, analyzed and interpreted data, drafted and revised the article. YX, ZMS, SG, KS, and LAR performed molecular experiments. FD, ZMS, and JKT performed histological and immunohistochemical experiments. FD and JKT analyzed pathological findings. JP, LAR, KS, HK, and MM performed serological analyses. FD, KAW, JCK, CAB, RZ, LG and CB performed statistical analyses. SJO, TDF, TCH, RCL, JCC, MEP, GEO, KJB, AVR, WDT, and SPL contributed autopsy tissue and plasma samples. FD, KAW, YX, JCK, and JKT performed data curation.
Competing interests: SJO has received funding from Agenus, Amgen, Biothera, Bristol Myers Squibb, Exicure, Genocea, Incyte, Merck, Ultimovacs, Viralytics. SJO has consulted for Biothera, Bristol Myers Squibb, BionTech, Exicure, Immunsys, Merck. KS is an inventor on a provisional U.S. patent application no. 63/092,350 entitled “Antibody specific for SARS-CoV-2 receptor binding domain and therapeutic methods.” The other authors declare no competing interests.