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"Surprised" at how "terrible" COVID-19 is to the body — that's how one pathologist characterized what she learned from autopsies of patients who died of the disease. And she is not alone.
COVID-19 has proven in some ways to be as mystifying to pathologists examining the dead as to physicians treating living patients. Despite raising more questions than answers, autopsy is still an important research tool, helping elucidate how the disease is causing injury and pointing to potential treatments.
Many hospitals and pathologists, for fear of infection and insufficient equipment, initially avoided conducting autopsies on those who had died from COVID-19. That logjam has broken and reports on how the SARS-CoV-2 virus affects the body have yielded both expected and unexpected findings.
"I was surprised at how bad it was," Amy Rapkiewicz, MD, chair of the Department of Pathology at NYU Langone Health's Winthrop Hospital in Mineola, New York, told Medscape Medical News. "The degree of respiratory disease was some of the worst I've ever seen," she said. "It's a terrible, terrible disease. Every organ in the body is pretty much affected."
Conducting COVID autopsies has been like going to a police lineup where one might not be able to definitively pick out the perpetrator but unlikely suspects can be eliminated, said Alex Williamson, MD, chief of autopsy pathology at New York's 23-hospital Northwell Health. "We've exonerated a lot of pathologies" so far, Williamson told Medscape Medical News.
"We've learned through autopsy that there's no direct tissue pathology to account for the acute symptoms that are seen" in the heart, the kidney, and the brain, said Williamson, a member of the College of American Pathologists' autopsy committee.
"That points us in the clinical investigative realm to finding other mechanisms for those processes, the goal being able to prevent them or treat them," he said.
Most reports have been small case studies from around the world, which are important to pointing out various potential pathologies, but don't have the heft of aggregate data, said Williamson. He's working on a study that will give a bigger picture from a dozen pathology sites in the United States and Brazil. It should be published by the fall, he said.
Pathologists have postulated a handful of hypotheses about the causes of extensive organ damage in COVID-19, including that hypoxia resulting from compromised lung function may be causing secondary injuries, said Williamson.
It's clear that obesity pre-disposes the infected to worse morbidity and mortality. "Obesity in and of itself is a pathologic state," he said, noting that it leads to atherosclerosis, increased clotting, fatty liver disease, and often, enlarged hearts. "If you now throw COVID into the mix, you're basically setting that person up for a high chance of a bad outcome," Williamson said.
Bennet Omalu, MD, MBA, MPH, who conducts autopsies for families, hospitals, and California's state health department in his private practice, said he has not seen anything unexpected, given the severe nature of the virus.
"SARS-CoV-2 is exhibiting a selectivity for the lungs," Omalu told Medscape Medical News. In one decedent, he observed a bone marrow response, "with many myeloid precursors in the peripheral blood vessels and tissues," which he said was typical in an overwhelming infection.
"The cells that SARS-CoV-2 may be targeting are the type II pneumocytes," he said. Those lung surface cells secrete a fatty substance to keep the lobes pliable. And that, Omalu notes, "precipitates the diffuse alveolar damage and acute respiratory failure that we are observing."
A May 21 report from the Centers for Disease Control and Prevention's COVID-19 Pathology Working Group on eight decedents from Washington state — seven of whom had been in a long-term care facility — had similar findings.
The authors note that immunohistochemistry testing and electron microscopy "confirmed viral tropism for pulmonary II pneumocytes." The overall pathologic features resembled those seen in SARS-CoV and MERS, the authors write.
They found, however, that viral antigen in lung tissue was higher than with SARS or MERS. "Extensive detection in epithelial cells of the upper respiratory tract is unique among these highly pathogenic coronaviruses," the CDC researchers explain.
COVID-19 autopsies have confirmed clinicians' reports of increased clotting. To Williamson, that indicates that "something is going on with endothelium and/or the blood clotting system of the body. The virus may very well be infiltrating the endothelium and causing injury to the blood vessel."
He said he has not seen endothelial injury as frequently as others, but added that it "is an important consideration in the pathophysiology of this virus."
Myocarditis is typical of viral diseases, but it has been frustratingly inconsistent in COVID-19 autopsies. Most have reported very little inflammation of the heart muscle. At least one death has been directly attributed to COVID-19–induced lymphohistiocytic and eosinophilic myocarditis.
And German researchers report in JAMA Cardiology that 60 of 100 patients who had recovered from COVID-19 had ongoing myocardial inflammation, as measured by cardiovascular magnetic resonance imaging (MRI).
Many collegiate football programs, reporting evidence of myocarditis in athletes who have recovered from COVID-19, said they would postpone their seasons.
"I suspect what they are seeing by [MRI] is not true myocarditis but something else," Richard S. Vander Heide, MD, PhD, MBA, a professor of pathology at Louisiana State University Health Sciences Center in New Orleans, told Medscape Medical News. Only biopsies can give definitive answers in the living, said Vander Heide, but so far, "autopsy studies have found no typical myocarditis in nearly every case."
Vander Heide and colleagues published cardiopulmonary findings from 10 autopsies conducted on African Americans who died from COVID-19 in The Lancet in May and updated it with an additional 12 cases in Circulation in July. Six of the 22 had a history of heart disease.
All had diffuse alveolar damage — a histopathologic marker of Acute Respiratory Distress Syndrome (ARDS) — in addition to pulmonary thrombi and microangiopathy. In all the cases, the virus was not found in the heart muscle cells and there was no evidence of what the authors called "typical lymphocytic myocarditis."
In the newer study, Vander Heide and colleagues used electron microscopy to find what appeared to be viral particles in the vascular cells in the heart, lungs, and kidneys.
Vander Heide, whose primary research interest is myocardial cell injury and adaptation, believes the infection of these endothelial cells is leading to clotting abnormalities in the heart's small vessels, causing inflammation. The heart cells are dying, but not from myocarditis, he said. Instead, he thinks it's likely that the clotting is causing cell death from ischemia.
Some pathologists are looking at vascular changes, which are "among the distinctive features of COVID-19," write Maximilian Ackermann, MD, and colleagues in an article published in May in the New England Journal of Medicine.
They compared lungs of seven patients who died from COVID-19 with seven who died from ARDS secondary to influenza, as well as those from 10 age-matched, uninfected patients. The COVID-19 lungs exhibited severe endothelial injury, which appeared to be associated with intracellular SARS-CoV-2 virus.
There also was widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries and significant new vessel growth from an unusual form of angiogenesis called intussusceptive angiogenesis — a reactive formation of new vessels where one splits into two, said co-author William W. Li, MD, president and medical director of the Angiogenesis Foundation.
In an accompanying editorial, Lida Hariri, MD, PhD, and C. Corey Hardin, MD, PhD, from Massachusetts General Hospital in Boston, say the angiogenesis theory "has to be considered speculative" and call for more research to determine if there is a true ARDS endotype in this subgroup.
Venous thromboembolism has also been observed in patients, including in a study at the University Medical Center Hamburg-Eppendorf in Germany that was published in May in the Annals of Internal Medicine.
"Coronavirus infections may be a trigger for venous thromboembolism," the authors write, citing several potential mechanisms, including endothelial dysfunction, systemic inflammation, and a pro-coagulatory state. "The direct activation of the coagulation cascade by a cytokine storm is conceivable," they write.
Researchers at Hospital Graz II in Graz, Austria, also homed in on thrombosis, with evidence of it in all 11 autopsies they conducted, according to an article published in Annals of Internal Medicine.
"We assume that these thrombotic events were disease-related and were the immediate cause of death," the authors explain, adding, "the mechanism[s] leading to pulmonary arterial thrombosis and coagulopathy in COVID-19 are not yet completely understood."
Pathologists were initially reluctant to take on COVID-19 autopsies, especially any that would involve aerosol-generating procedures. The College of American Pathologists attempted to allay fears with guidelines that recommend techniques that minimize those procedures, including using hand shears or other alternatives to an oscillating bone saw (also recommended by the CDC) or using a vacuum shroud with the bone saw.
Williamson pointed out that there have been no reported cases of SARS-CoV-2 transmission from a corpse to any pathologist, morgue technician, or assistant. Still, his informal survey in March of pathologists on a LISTSERV he manages found that only six out of 50 respondents were conducting autopsies. A month later, that number had risen to 30.
NYU Langone Health was hesitant because of infection risk and a desire to conserve personal protective equipment (PPE), Rapkiewicz said. Plus, the Occupational Safety and Health Administration's initial recommendations were to avoid autopsies in patients with known COVID-19.
"That gave everybody the reason not to do them," Rapkiewicz said.
However, NYU critical care clinicians wanted knowledge from autopsies. Rapkiewicz and the autopsy director at NYU's Tisch Hospital presented administrators with a protocol to mitigate risk, one that dictated they wash the body with bleach, skip full brain exams, keep residents from participating, and conserve PPE by doing only two autopsies per week at each hospital. The administration relented.
"There was a little too much fear and not enough critical analysis early on," said Williamson. "But if you isolate the emotional aspect of COVID-19 from the fact, it's an infectious disease like other infectious diseases."
Still, pathologists are taking precautions. The CDC recommends autopsies be done in a negative pressure suite, which are more common at academic centers.
Omalu has devised a system to do the autopsy while the decedent is still in a body bag. He uses disposable medical towels to wipe and clean the body, and a powered suction tool to suck up any oozing blood.
Towels or N95 masks are placed over the body's nose and mouth, whereas towels atop the larynx, pharynx, trachea, and bronchi during dissection reduce aerosolization. Omalu and his staff wear disposable suits, N95 masks or respirators, face shield and goggles, and heavy-duty gloves.
With so many unknowns, Omalu still assumes he has been or will be exposed. "I stopped hugging and kissing my wife and children," he said, adding that he wears a mask at home and uses a separate bathroom and bedroom in a different part of his house.
Omalu and other pathologists said that, despite the potential for exposure to SARS-CoV-2, it is crucial that autopsies continue.
"The autopsy remains a vital medical research tool even in the 21st century, especially during this era when medical students are no longer adequately exposed and trained in the pathological sciences and the pathological basis of disease," Omalu explained.
"Autopsy is about the dead helping the living," said Williamson. "What we learn from someone who has died from an illness helps us better manage the people that have yet to contract that illness."
Williamson has been encouraging the 200 or so pathologists who subscribe to his LISTSERV to share information.
"COVID is a wake-up call that, wow, we really are benefiting from having competent autopsy practice and performance in place for this pandemic," said Williamson.
"Autopsy pathology has been facing extinction for many decades," he explained. "We need to be sure that we're ensuring that there is a generation of autopsy pathologists 20 or 30 years from now for COVID 3 or whatever that next pandemic is going to be."
