Dr. Megan Ranney has learned a lot about Covid-19 since she began treating patients with the disease in the emergency department in February.
But there’s one question she still can’t answer: What makes some patients so much sicker than others?
Advancing age and underlying medical problems explain only part of the phenomenon, said Ranney, who has seen patients of similar age, background and health status follow wildly different trajectories.
“Why does one 40-year-old get really sick and another one not even need to be admitted?” asked Ranney, an associate professor of emergency medicine at Brown University.
In an international study in Science, 10 percent of nearly 1,000 Covid-19 patients who developed life-threatening pneumonia had antibodies that disable key immune system proteins called interferons. These antibodies — known as autoantibodies, because they attack the body itself — weren’t found at all in 663 people with mild or asymptomatic Covid-19 infections. Only four of 1,227 healthy patients had the autoantibodies. The study was led by the Covid Human Genetic Effort, which includes 200 research centers in 40 countries.
“This is one of the most important things we’ve learned about the immune system since the start of the pandemic,” said Dr. Eric Topol, executive vice president for research at Scripps Research in San Diego, who wasn’t involved in the new study. “This is a breakthrough finding.”
In a second Science study by the same team, the authors found that an additional 3.5 percent of critically ill patients had mutations in genes that control the interferons involved in fighting viruses. Given that the body has 500 to 600 of those genes, it’s possible that researchers will find more mutations, said Qian Zhang, lead author of the second study.
Interferons serve as the body’s first line of defense against infection, sounding the alarm and activating an army of virus-fighting genes, said virologist Angela Rasmussen, an associate research scientist at the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health.
“Interferons are like a fire alarm and a sprinkler system all in one,” said Rasmussen, who wasn’t involved in the new studies.
Lab studies show that interferons are suppressed in some people with Covid-19, perhaps by the virus itself.
Interferons are particularly important for protecting the body against new viruses, such as the coronavirus, which the body has never encountered, said Zhang, a researcher at Rockefeller University’s St. Giles Laboratory of Human Genetics of Infectious Diseases.
When infected with the novel coronavirus, “your body should have alarms ringing everywhere,” Zhang said. “If you don’t get the alarm out, you could have viruses everywhere in large numbers.”
Significantly, patients didn’t make autoantibodies in response to the virus. Instead, they appeared to have had them before the pandemic even began, said Paul Bastard, the antibody study’s lead author, who is also a researcher at Rockefeller University.
For reasons that researchers don’t understand, the autoantibodies never caused a problem until patients were infected with Covid-19, Bastard said. Somehow, the coronavirus, or the immune response it triggered, appears to have set them in motion.
“Before Covid, their condition was silent,” Bastard said. “Most of them hadn’t gotten sick before.”
Bastard said he hopes his findings will lead to new therapies that save lives. He noted that the body manufactures many types of interferons. Giving patients a different type of interferon — one not disabled by their genes or autoantibodies — might help them fight off the virus.
In fact, a pilot study of 98 patients published Thursday in the Lancet Respiratory Medicine journal found benefits from an inhaled form of interferon. In the industry-funded British study, hospitalized Covid-19 patients randomly assigned to receive interferon beta-1a were more than twice as likely as others to recover enough to resume their regular activities.
Around the world, scientists have launched more than 100 clinical trials of interferons, according to clinicaltrials.gov, a database of research studies from the National Institutes of Health.
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