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A detailed histologic study of lungs obtained at autopsy from patients with COVID-19 reveals some potential clues as to how the virus damages blood vessels and why it might be so much more deadly than influenza.
The small study, which involved just seven lungs from patients who died of confirmed COVID-19 and seven lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to H1N1 influenza in 2009, showed three distinctive features of COVID-19:
severe endothelial injury associated with intracellular SARS-CoV-2 virus and disrupted endothelial cell membranes
widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries
significant new vessel growth through a mechanism they refer to as intussusceptive angiogenesis.
"I think the take-home message here is that this is a respiratory virus that causes a vascular disease, and the damage to the blood vessels explains a lot of the systemic organ failure and death that we've seen in these patients," said thoracic surgeon Steven J. Mentzer, MD, Harvard Medical School, Boston.
He and colleagues, including first author Maximilian Achermann, MD, University of Witten-Herdecke, Wuppertal, Germany, published their findings online on May 21 in the New England Journal of Medicine.
"In particular, the endothelial damage we saw is an important observation that may explain a fair number of clinical observations," Mentzer suggested in an interview.
He was cautious to suggest how these findings might change or determine current treatments.
Although lungs from influenza sufferers also showed diffuse alveolar damage, Mentzer noted that in the COVID-19 lungs, there were 9-fold as many segments occluded by microthrombi (P < .001).
"Although tissue hypoxia was probably a common feature in the lungs from both these groups of patients, we speculate that the greater degree of endothelialitis and thrombosis in the lungs from patients with COVID-19 may contribute to the relative frequency of sprouting and intussusceptive angiogenesis observed in these patients," Mentzer and colleagues write.
The amount of angiogenesis seen was unexpected, he said, and about 2.7-fold higher than that seen in lungs from patients with influenza (P < .001).
The study was conducted by a team of researchers from Europe and the United States who used multiple means to qualify and quantify the lungs of COVID-19 patients, compared with those from influenza patients and 10 age-matched, uninfected control lungs.
All lungs were analyzed with the use of microcomputed tomographic imaging, seven-color immunohistochemical analysis, transmission and scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression.
"It's an exhaustive, focused look at a very small number of patients," said Mentzer in an interview. "For a variety of social and public health reasons, autopsies really are not common in COVID-19, so this was a unique resource and we did about 3 years of work in 2 months."
ARDS by Another Name?
In an editorial, Lida Hariri MD, PhD, and C. Corey Hardin, MD, PhD, both from Massachusetts General Hospital in Boston, took issue with the "uniqueness" of the study's findings, saying that "temporal heterogeneity complicates any direct comparison."
Because the groups were sampled at different stages of the disease and given the clinical differences between the groups (none of the COVID-19 patients were intubated but most of the influenza patients had been intubated and treated with ventilator settings that are now considered lung damaging), Hariri and Hardin suggest that the findings do not differentiate the two diseases to the extent suggested by Mentzer et al, but more describe the heterogeneity of the clinical syndrome of ARDS.
"The investigators' conclusion that 'vascular angiogenesis distinguished the pulmonary pathobiology of COVID-19 from that of equally severe influenza virus infection' has to be considered speculative," they conclude.
Jeffrey Weitz, MD, director of the Thrombosis & Atherosclerosis Research Institute at McMaster University in Hamilton, Ontario, Canada, is inclined to agree.
"Stepping back, the most important aspect of the paper to my mind is the confirmation of endothelial damage, which may be the root cause of the coagulopathy and likely contributes to the pathology," he said in an interview.
"Since endothelial cells express the ACE2 receptor and alveolar endothelial cells in the lung lie in close proximity to the alveolar epithelial cells into which the virus first enters, it is not surprising that both cell types become infected."
The challenge, Weitz said, is how to turn off endothelial cell activation. "I don't think there are any real surprises here, but I think the endothelial dysfunction is a definite problem because we really don't have good therapies to fix the endothelium."
Weitz thinks most centers are giving hospitalized COVID-19 patients heparin at this point. "Everybody is probably getting prophylactic doses and we've gone a little bit more aggressively and we're giving weight-adjusted prophylactic doses, given that obesity is definitely a risk factor for COVID-19."
He also said trials are ongoing in this area, including a trial of extended anticoagulation after hospital discharge.
"If you think about the risk factors for this disease, it's hypertension, diabetes, age — the same vascular risk factors we see in cardiology. It's not the respiratory risk factors like a history of asthma necessarily or COPD that seem to increase your chance of having a bad outcome or to get some disease," noted Weitz.
Weitz also took issue with the use of the term endothelialitis. "The endothelium isn't surrounded by inflammatory cells to think that this is some sort of vasculitis. It's not."
Mentzer reported he is the recipient of NIH grants. None of the authors reported conflicts of interest relevant to this article.
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Cite this: Autopsy Data Show Extensive Lung Damage From COVID-19 - Medscape - May 26, 2020.