In late March, Mary Beth Beasley, MD, head of pulmonary pathology at Mount Sinai Health System, began getting concerned calls from pulmonologists that the acute respiratory disease syndrome (ARDS) they were seeing in their sickest COVID-19 patients was behaving differently than the usual sepsis-related ARDS. Indeed, radiologic evaluation of COVID-19 cases was showing findings more akin to organizing pneumonia, and many patients retained high levels of respiratory compliance in spite of the presence of severe hypoxemia, which is atypical in classic ARDS.
Determined to help unravel the many mysteries around this unpredictable virus, Dr. Beasley teamed up with colleagues at New York-Presbyterian/Weill Cornell Medicine and Padua University Hospital in Italy to investigate the histologic features of 68 patients who had died from COVID-19. What their retrospective study, reported in Modern Pathology, confirmed was a complex pulmonary pathology with multiple pathways and cytokines that reinforced the growing awareness by pulmonologists of the complexity of COVID-19 and its progression.
“Pathologically, we found a consistent pattern of diffuse alveolar damage, or acute lung injury, as well as vascular/thrombotic disease in patients with comorbidities such as hypertension and diabetes,” says Dr. Beasley, Professor of Pathology, Molecular, and Cell-Based Medicine, and Medicine, at the Icahn School of Medicine at Mount Sinai and senior author of the study. Particularly noticeable to researchers was the frequency of large vessel thrombi, seen in 42 percent of autopsied lungs, as well as the frequent presence of tracheobronchial inflammation and the histologic features of diffuse alveolar damage at different stages of the disease. Taken together, these findings suggested to Dr. Beasley “upper airway to alveolar progression, alongside unique vascular and thrombosis-induced injury.”
The clinical and histologic findings of the study were similar at each of the three participating institutions in the United States and Italy, which had been a European coronavirus hotspot. Moreover, the researchers found a relatively low rate of coronavirus among current smokers, in contrast to other studies reporting that smoking and chronic obstructive pulmonary disease were associated with disease progression and poor outcomes in COVID-19. The research team concluded that smoking could still be an important comorbidity along with diabetes, hypertension, and other disorders to produce a harmful cumulative effect on patients, and called for additional studies.
More convincing to Dr. Beasley and her colleagues was the key role that vasculature of the lungs and other organs played in COVID-19 disease pathogenesis. This wasn’t altogether surprising to them since SARS-CoV-2, the virus that causes COVID-19, is a coronavirus that uses angiotensin converting enzyme 2 (ACE-2) receptors as a means of cellular entry, just as the coronavirus agents SARS and MERS do. ACE-2 is also expressed in lung alveolar cells and bronchial epithelium and vascular endothelial cells, explaining why the respiratory tract and lungs serve as a primary point of viral entry. Indeed, while COVID-19 has been shown to impact a variety of organs, respiratory system pathology predominates, with mortality linked primarily to acute respiratory distress syndrome.
Another noteworthy finding from the lung pathology study concerned neutrophil granulocytes. While neutrophils may reflect superinfection and ventilator-associated pneumonia, a subset of cases the researchers examined showed rapid progression to severe respiratory failure without evidence of those two phenomena. This suggested to the team the ability of neutrophils to release neutrophil extracellular traps to drive acute tracheobronchitis, ARDS, and thrombosis, and that blocking their formation might be an avenue to ameliorating the severity of COVID-19 in at least a subset of patients.
In highlighting the challenges of a pulmonary disease that impacts compartments ranging from upper airway to lung parenchyma to the vascular bed, the Mount Sinai-led study could help to inform future clinical management of COVID-19, emphasizes Dr. Beasley. “I’m hopeful,” she says, “that even without isolating something unique to COVID-19, our work will teach us a lot more about ARDS and, particularly, how to manage different phenotypes of these patients.”
Mary Beasley, MD
Professor of Pathology, Molecular and Cell-Based Medicine, and Medicine