Ackermann M, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2015432.
Hariri L, et al. N Engl J Med. 2020;doi:10.1056/NEJMe2018629.
Patients who died from COVID-19-associated respiratory failure had more intussusceptive angiogenesis in their lungs than those who died from influenza, according to an autopsy study.
For the study, which was published in The New England Journal of Medicine, researchers used seven-color immunohistochemical analysis, micro-CT imaging, scanning electron microscopy, corrosion casting and direct multiplexed measurement of gene expression to evaluate and compare lungs from patients who died from COVID-19 with those who died from influenza A (H1N1)-associated acute respiratory distress syndrome in 2009 and those from age-matched uninfected controls.
Results revealed some similarities between the lungs from patients with COVID-19 and influenza pneumonia, including diffuse alveolar damage, greater expression of angiotensin-converting enzyme 2 (ACE2) expression and presence of ACE2-positive lymphocytes in perivascular tissue, as compared with lungs from uninfected controls. Lungs from both the COVID-19 and influenza groups also had similar mean numbers of CD3+ T cells within a 200-µm radius of precapillary and postcapillary vessel walls in 20 fields of examination per patient, with some differences in the number of CD4+, CD8+ T cells and neutrophils among patients with COVID-19 vs. influenza.
The researchers also noted that 79 inflammation-associated genes were differentially regulated only in lungs from the COVID-19 group, two were differentially regulated only in lungs from the influenza group and seven had a shared expression pattern.
Thrombi in pulmonary arteries were found in four of seven lungs from patients with COVID-19 and four of seven lungs from patients with influenza. Alveolar capillary microthrombi, however, were nine times more prevalent among specimens in the COVID-19 group vs. the influenza group (P < .001).
Additionally, the researchers found that the amount of new vessel growth was 2.7 times higher, primarily due to intussusceptive angiogenesis, in lungs from patients with COVID-19 than in lungs from patients with influenza (P < .001).
Further analysis also showed 69 angiogenesis-related genes were differentially regulated only in the COVID-19 group, 26 were differentially regulated only in the influenza group and 45 had shared changes in expression.
“In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of COVID-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observation require further research to define,” the researchers wrote.
In an accompanying editorial, Lida Hariri, MD, PhD, and C. Corey Hardin, MD, PhD, both from Massachusetts General Hospital in Boston, highlighted some of the study’s limitations, including its small sample size. Furthermore, most of the patients with influenza vs. none with COVID-19 were intubated and treated with ventilator settings that would now be deemed not protective of the lungs and the lungs were sampled at different stages of disease. Consequently, they noted, the researchers’ conclusions should be considered speculative, as these data do not provide enough evidence to firmly define differences between COVID-19 and influenza.
“This study emphasizes the heterogeneity that is fundamental to the clinical syndrome of ARDS, which affects not only prognosis and potential treatment response but also the interpretation of clinical trials. Future studies are needed to determine whether these reported differences in angiogenesis represent distinct time points in a similar disease process or a true endotype that occurs only in a subgroup of patients,” Hariri and Hardin wrote. “Regardless, the finding of a novel pathological process opens up the possibility of developing sorely needed new treatments and should spur further research. In this work, Ackermann and colleagues have made an important contribution that may ultimately lead to a greater understanding of ARDS endotypes.” – by Melissa Foster
Disclosure: This study was funded by the NIH. Ackermann reports he has received grants from the NIH. Please see the study for all other authors’ relevant financial disclosures. Hardin reports he has received grants from AstraZeneca. Hariri reports she has received personal fees from Biogen Idec, Boehringer Ingelheim and Pliant Therapeutics.