By Jason Gale

In an air-locked chamber in the world’s largest research hospital, Daniel Chertow and a half-dozen doctors and scientists clad in astronaut-inspired protective gear are carrying out a microscopic search inside a 26-year-old man.

The patient went to the hospital with chest pain in spring 2020. He didn’t have typical Covid-19 symptoms, but Chertow wants to study him as part of a broader mission to understand where in the body the coronavirus goes and what it does in each of those places. If you’re a Covid case in Chertow’s emerging pathogens lab, you’re not there for treatment; you’re the subject of an autopsy.

The man died at the hospital and tested negative for SARS-CoV-2, so he doesn’t fit the definition of a Covid-related fatality. He succumbed to viral myocarditis, or inflammation of the heart muscle. Chertow’s sleuthing points to the coronavirus as the culprit and offers clues about a rare inflammatory condition that occurs mostly in children after a mild case of Covid.

“They show up later with sometimes life-threatening inflammation in different organs,” Chertow says over Zoom from his office at the National Institutes of Health’s Clinical Center in Bethesda, Md. “In a way, he fits into that category, so what’s driving that?”

An autopsy provides a snapshot of what’s occurred at the moment a patient has died, enabling pathologists to infer what happened up to that point. By comparing a large number of autopsies on Covid patients at different time courses, scientists can begin to assemble something akin to a record of the virus’s journey through the body and the disease that arose in its wake.

Autopsies were a cornerstone of medical discoveries for more than two millennia, but sophisticated diagnostic tools and health-system budget cuts have made them a dying practice. Among the first 4 million fatal Covid cases worldwide, only several hundred autopsy findings were reported in international medical journals.

Several scientists are pushing to raise those numbers. “It’s critically important that thousands of autopsies are done, so we can put this picture together,” says Jeffery Taubenberger, a pathologist who heads the viral pathogenesis and evolution section of the National Institute of Allergy and Infectious Diseases in Bethesda. “What we’re trying to figure out here is, what goes wrong under the worst circumstances where people die—to try to understand how the virus causes disease in less severe cases. And then: What are the therapeutic implications of that?”

The National Institutes of Health is spending $1.15 billion over four years to learn about the aftereffects of Covid-19, including a push to conduct more autopsies. Answers are urgently needed. At least 1 in 10 survivors of the disease experience what the World Health Organization calls “post Covid-19 condition”—a constellation of symptoms that can debilitate sufferers for months.

“The post-Covid stuff is very, very real,” says Chertow, a 47-year-old critical care physician. “If you’re going to begin to conceive of ways to prevent or treat those manifestations, you need to understand what’s driving it.”

Authorities were concerned in the panic-stricken early months of the pandemic that dissecting coronavirus-infected patients could spread the infection, resulting in at least half of the autopsy units in the U.S. being shut down, according to L. Maximilian Buja, a professor of pathology and laboratory medicine at the University of Texas’s McGovern Medical School in Houston.

Buja, who finished his pathology training in 1972, co-led a call to action for detailed autopsies on Covid victims in April 2020 and kept his own academic center’s autopsy suites open. That enabled him to report findings from one of the earliest autopsy case series that showed the propensity for the coronavirus to cause tiny clots to form in patients’ blood.

“I take some credit, or partial credit, for getting across the idea that clinically, we need to institute early anticoagulation therapy,” he says. “We have glimmers of knowledge that have contributed to improved treatment for the patients, but there’s a lot more we have to learn. The key to this is to continue to do the autopsy investigations.”

Hamburg forensic pathologist Klaus Puschel defied Germany’s official recommendation to avoid autopsies, permitting 80 comprehensive post-mortem exams on fatal cases in March and April 2020. The findings showed SARS-CoV-2 can spread beyond the respiratory tract to affect the heart, kidney, liver, and brain.

A study Puschel co-authored that was published in October based on 17 autopsies showed the infection was associated with an increased number of defective capillaries in the brain that may explain the cognitive impairment, memory deficits, and fatigue experienced by at least a subset of long Covid patients. The authors also found that an experimental drug known as a RIPK1 inhibitor could potentially avert the damage if given to Covid patients during the acute phase of the illness.

Researchers in Norway showed in July that individuals who tested positive for the coronavirus eight months earlier were almost five times more likely than uninfected people to report memory problems. The NIH’s Chertow says he’s concerned about what such health effects may lead to in the future.

“Is there going to be some subclinical effects on your brain that are going to cause neurocognitive issues later in life that perhaps are not immediately noticeable or detectable?” he says. “If you’re going to begin to conceive of ways to prevent or treat those manifestations—either in the next group that might be exposed or among the group that are suffering—you need to understand what the drivers are.”

Chertow, who also trained as a disease detective with the Centers for Disease Control and Prevention’s epidemic intelligence service, says he was inspired to pursue autopsy research from studying Ebola and treating patients with the deadly disease in Liberia in 2014. “It started with this idea that first [we’ve] got to go find where this virus is going—what it’s doing in those places—and then we’ve got to try to link it back to what we’re seeing clinically.”

Chertow helped identify the role of the salivary glands in SARS-CoV-2 transmission. He sees more valuable clues about the virus’s distribution across the body among the more than 10,000 biospecimens his team has collected from 44 fatal cases since April 2020. The post-mortem exams and dissections take three hours in a secure facility that’s required for work involving microbes that can cause serious and potentially lethal disease. Bioengineers on the NIH campus custom-built an enclosure that fits over the head and shoulders of the deceased to contain aerosols when the top of the skull is removed.

The seven or so doctors, scientists, and technicians working inside the autopsy suite wear multiple layers of personal protective equipment, says David Kleiner, chief of the post-mortem section of the National Cancer Institute, who worked with Chertow on the research. Usually a plastic apron is worn over a surgical gown, over an impermeable coverall, over surgical scrubs. Sometimes arm-sleeve protectors are worn. Investigators also don three pairs of gloves and two pairs of shoe coverings. And instead of N95 face masks, they breathe through controlled air-purifying respirators, which provide HEPA-filtered air under a hood that fits over their head and shoulders.

It’s cumbersome, but that’s not the only aspect of these Covid autopsies that makes the work painstaking. “We’re sampling way above and beyond what is done in any sort of typical autopsy,” Chertow says. Samples are taken from almost 100 different regions of the body and brain.

And for each one of those areas, adjacent pieces of tissue are also collected and preserved in different ways that are amenable to different methods of analysis, including whether the virus is capable of replicating in the sites from which it’s collected. “We’ve done, simply put, a much more extensive sampling than others have,” he says.

That partly reflects the diminishing capability to perform autopsies outside of academic and medical examiner settings.

“Autopsies are expensive procedures,” says Linda Isles, head of forensic pathology services at the Victorian Institute of Forensic Medicine in Melbourne. “In reality, not many people want to spend money on dead people.” Private autopsy fees vary widely, but typically cost $2,000 to $4,000 in Maryland.

Doctors are ordering fewer autopsies, relying instead on lower-cost X-rays, MRI scans, and other tests to ascribe the cause of a patient’s death. This means pathologists have less experience performing post-mortem exams. In addition, autopsy facilities are expensive to maintain at a safe standard, Isles says.

“So it’s this spiral of decreased experience—and therefore decreasing confidence—and then underutilization of the facilities leading to some of the facilities essentially being mothballed,” she says. “And then when you want to reinstitute them, they’re no longer really safe for modern practice.”

Isles, who finished medical school at the University of Tasmania more than 20 years ago, performed 200 to 300 autopsies during her pathology training. “That might not seem like very many,” she says, “but if you compare that to anatomical pathology trainees now, then that is a very large amount.”

In 1918, doctors performed thousands of autopsies on victims of the Spanish flu and shared their findings widely in illustrated reports, says Taubenberger at the National Institute for Allergy and Infectious Diseases. “It’s terrible that here we are with our ability to do advanced molecular studies and advanced imaging studies, and yet so few autopsy studies are being done,” he says. “That’s really the tragedy.”