COVID-19 Autopsies Put Endothelial Damage, Angiogenesis in the Spotlight
The still-forming picture suggests significantly more new-vessel growth in the lung than would be expected from a typical flu.
More autopsy reports on COVID-19 patients, some from the United States, are helping researchers piece together a picture of a virus that damages endothelial cells, causing a clotting disorder that can lead to deep vein thrombosis and pulmonary emboli.
“These people are in a hypercoagulant state, and early anticoagulation is important,” said Louis Maximilian Buja, MD (UTHealth, Houston, TX), lead author on a recent autopsy paper in Cardiovascular Pathology. “I think what's going to happen is some kind of cocktail of combined therapies is going to evolve that’s going to give these people a better shot at surviving compared to just the respirator alone.”
As TCTMD recently reported, German researchers looking at 12 autopsies of COVID-19 patients found a substantial number of deaths were related to pulmonary embolism despite the patients having no prior evidence of thrombosis. In their autopsy study of patients from five centers in the United States, Buja and colleagues report major pulmonary thromboemboli with pulmonary infarcts and/or hemorrhage in five of 23 patients and a pattern of cardiac comorbidity similar to what was seen in the German study.
“The pathogenesis of COVID-19 pulmonary disease involves binding of SARS-CoV-2 virus to ACE2 receptors to pneumocytes and endothelial cells, leading to development of acute lung injury manifest as [diffuse alveolar damage],” they write.
To TCTMD, Buja said the autopsy data clarify that endothelial damage leads to “essentially a clotting disorder in the capillaries of the lungs.” Another autopsy report, published online May 21, 2020, in the New England Journal of Medicine, appears to corroborate that theory. Led by Maximilian Ackermann, MD (Helios University Clinic Wuppertal, Germany), the study compared seven lungs from COVID-19 patients with seven lungs of patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A (H1N1) and 10 age-matched, uninfected control lungs. As with the Buja study, they found a preponderance of severe endothelial injury in the COVID-19 lungs, as well as widespread thrombosis with microangiopathy.
“We found greater numbers of ACE2-positive endothelial cells and significant changes in endothelial morphology, a finding consistent with a central role of endothelial cells in the vascular phase of COVID-19,” Ackermann and colleagues write. The damaged endothelial cells showed disruption of intercellular junctions, swelling, and loss of contact with the basal membrane.
Compared with the patients who died secondary to influenza A, the COVID-19 patients had nine times the prevalence of capillary microthrombi (P < 0.001) and their amount of angiogenesis in the lungs was 2.7 times higher (P < 0.001). Ackermann and colleagues theorize that the mechanism behind the growth in the lungs is likely intussusceptive angiogenesis, caused by either endothelial injury and thrombosis in the lungs and/or a chronic hypoxic state.
In an accompanying editorial, Lida Hariri, MD, PhD, and C. Corey Hardin, MD, PhD (both from Massachusetts General Hospital, Boston), call the findings “intriguing” but say that while it is tempting to ascribe the new cell growth seen in the lungs as being specific to SARS-CoV-2 and COVID-19, there are too many fundamental differences between the groups being compared to draw firm conclusions.
“Nevertheless, this observation of angiogenesis in an early stage of diffuse alveolar damage is important,” Hariri and Hardin write. Although it will be crucial to understand how angiogenesis aligns with the COVID-19 disease course, “the finding of a novel pathological process opens up the possibility of developing sorely needed new treatments and should spur further research,” they add.
Autopsies and Corroboration in the COVID-19 Era
A major problem right now is the paucity of autopsy data, which stems both from health concerns for those who perform the autopsies and from government regulations. In the United States, mixed messages from regulatory authorities such as the Occupational Safety and Health Administration (OSHA) early on in the pandemic may have fueled confusion and delays.
“Initially, OSHA came out with a guideline saying that autopsies should not be done on COVID patients, and then there was pushback [so] it was reversed to say basically ‘be careful,’” Buja observed. The Centers for Disease Control and Prevention also issued guidelines for morgues and autopsy facilities and advised that professional judgment be used with regard to “whether postmortem testing is necessary.”
While some hospitals have closed their autopsy units for the time being, Buja said he has pushed for his to stay open, citing the need to advance understanding of the underlying pathologies. Still, the number of cases of completed autopsies among COVID-19 deaths are small, which has led to an effort to collate them into a listserv.
Even with appropriate personal protective equipment, there is concern for those performing autopsies on deceased COVID-19 patients. In a letter to the editor of the Journal of Forensic and Legal Medicine, a physician from Thailand and one from China report what they say is the first case of a workplace exposure to COVID-19 among a forensic practitioner working in Bangkok. Another letter, published in JAMA, may add further to the concerns by demonstrating that the virus persists in the respiratory tract after death.
As it is, pulmonologists are wary of doing transbronchial biopsies because it increases their personal risk. But the biopsies would likely help to correlate the pathology findings from the autopsies and further the science at a time when it is especially crucial, Buja noted.
“We really could benefit by some courageous pulmonologists trying to do serial biopsies,” he concluded.
Buja LM, Wolf DA, Zhao B, et al. The emerging spectrum of cardiopulmonary pathology of the Coronavirus Disease 2019 (COVID-19): report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities. Cardiovasc Pathology. 2020;Epub ahead of print.
Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in COVID-19. N Engl J Med. 2020;Epub ahead of print.
Hariri L, Hardin CC. Covid-19, angiogenesis, and ARDS endotypes. N Engl J Med. 2020;Epub ahead of print.
Schaller T, Hirschbühl K, Burkhardt K, et al. Postmortem examination of patients with COVID-19. JAMA. 2020;Epub ahead of print.
- Buja and Schaller report no relevant conflicts of interest.
- Ackermann reports grants from the NIH during the conduct of the study.
- Hardin reports grants from Astra-Zeneca.
- Hariri reports personal fees from Pliant Therapeutics, personal fees from Biogen Idec, and grants and personal fees from Boehringer Ingelheim.