Studies offer clues as to why some COVID-19 patients die

Dr. Megan Ranney has learned a lot about COVID-19 since she began treating patients with the disease in the emergency room in February.

But there is a question he still can’t answer: What makes some patients so much sicker than others?

Advanced age and underlying medical problems explain only part of the phenomenon, said Ranney, who has seen patients of similar ages, backgrounds, and health status follow wildly different trajectories.

“Why does a forty-year-old get really sick and another doesn’t even need to be hospitalized?” asked Ranney, an associate professor of emergency medicine at Brown University.

Challenging new research shows that in some cases some people – men in particular – succumb because their immune systems are hit by friendly fire. The researchers hope the discovery will help them develop targeted therapies for these patients.

In an international study Published last month in the journal 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, have not been found in 663 people with mild or asymptomatic coronavirus infections. In fact, only four of the 1,227 healthy individuals had the autoantibodies.

“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 of research at Scripps Research in San Diego, who was not involved in the new study. “This is a revolutionary discovery.”

In a second science study, the same team or researchers found that an additional 3.5% of critically ill patients had mutations in the genes that control the interferons involved in the fight against viruses. Given that the body has 500 to 600 of these 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 infections, raising the alarm and activating an army of virus-fighting genes, said virologist Angela Rasmussen, an associate researcher at the Mailman School of Public Health’s Infection and Immunity Center. Columbia University.

“Interferons are like a fire alarm and irrigation system all in one,” said Rasmussen, who was not involved in the new studies.

Laboratory studies show that interferons are suppressed in some people with COVID-19, possibly by the virus itself.

Interferons are especially important for protecting the body from new viruses, said Zhang, a researcher at Rockefeller University’s St. Giles Laboratory of Human Genetics of Infectious Diseases.

When he was infected with the new coronavirus, “your body should have alarms going off everywhere,” he said. “If you don’t go off the alarm, you could have viruses everywhere in large numbers.”

Significantly, the patients did not produce autoantibodies in response to the virus. Instead, they appeared to have had them before the pandemic even started, said Paul Bastard, lead author of the first study and a researcher at Rockefeller University.

For reasons the researchers don’t understand, autoantibodies never caused a problem until patients were infected with COVID-19, Bastard said. Somehow, the new coronavirus, or the immune response it triggered, appears to have set them in motion.

“Before COVID, their conditions were silent,” he said. “Most of them weren’t sick before.”

Scientists have long known that viruses and the immune system compete in something of an arms race, with viruses evolving ways to evade the immune system and even suppress its response, said Sabra Klein, professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School. of public health.

Antibodies are usually the heroes of the immune system, defending the body from viruses and other threats. But sometimes the immune system appears confused and creates autoantibodies. This occurs in autoimmune diseases such as rheumatoid arthritis, when antibodies attack the joints e Type 1 diabetes, in which the immune system attacks the insulin-producing cells in the pancreas.

Although doctors don’t know the exact causes of the autoimmune disease, they have observed that the conditions often occur later a viral infection.

In another unexpected result from the first study, 94% of the patients with these autoantibodies were men. About 12.5 percent of men with life-threatening COVID-19 pneumonia had autoantibodies to interferon, compared with 2.6 percent of women. It was unexpected, as autoimmune disease is a long way off more common in women, Klein said.

“I’ve been studying sex differences in viral infections for 22 years, and I don’t think anyone who studies autoantibodies thought this would be a risk factor for COVID-19,” he said.

The study could help explain why men are more likely than women to become seriously ill with COVID-19 and die, Klein said.

“You see a lot more men dying in their 30s, not just their 80s,” he said.

Akiko Iwasaki, a professor of immunobiology at Yale School of Medicine, noted that several genes involved in the immune system’s response to viruses are on the X chromosome.

Women have two copies of this chromosome, along with two copies of each gene it contains. This provides women with a backup in case one copy of a gene becomes defective, Iwasaki said.

Men, however, only have one copy of the X chromosome. So, if there is a defect or a harmful gene on the X chromosome, they have no other copy of that gene to correct the problem, Iwasaki said.

Bastard noted that a woman in the study who developed autoantibodies has a rare genetic condition where she only has one X chromosome.

Scientists have struggled to explain why men have a higher risk of hospitalization and death from COVID-19. When the disease first appeared in China, experts speculated that men suffered more from the virus because they are much more likely to smoke than Chinese women.

The researchers quickly noted that men in Spain were also more likely to die from COVID-19, however, even though men and women smoked at roughly the same rate, Klein said.

But the behavioral differences between men and women provide only part of the answer. Scientists say it’s possible that the hormone estrogen may somehow protect women, while testosterone may put men at greater risk. Interestingly, recent studies have found that obesity accounts for a much greater risk for men with COVID-19 than women, Klein said.

To be sure, scientists say the new research solves only part of the mystery of why patient results can vary so greatly.

It is possible that some patients are protected from past exposure to other coronaviruses. Patients who become seriously ill may also have inhaled higher doses of the virus, for example due to repeated exposure to infected colleagues.

Screening patients for autoantibodies to interferons could help predict which patients are most likely to become seriously ill, Bastard said. The test takes about two days.

“I think we should give the test to everyone who is admitted,” he said.

Bastard said he hopes his findings will lead to new therapies that will save lives. He notes that the body produces many types of interferons, and giving patients a different type that isn’t disabled by their genes or autoantibodies could help them fight the virus.

A pilot study of 98 patients published Thursday in the journal Lancet Respiratory Medicine found benefits from an inhaled form of interferon. In the industry-funded 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 normal activities.

Researchers need to confirm these findings in a much larger study, said Dr Nathan Peiffer-Smadja, a researcher at Imperial College London who was not involved in the research but wrote an accompanying editorial. Future work should test patients’ blood for genetic mutations and autoantibodies to interferon to see if they respond differently from others.

Around the world, scientists have initiated more than 100 clinical trials of interferons. Until larger studies are completed, doctors say, Bastard’s findings are unlikely to change the way they treat COVID-19.

Dr. Lewis Kaplan, president of the Society of Critical Care Medicine, said he treats patients based on their symptoms, not their risk factors.

“If you’re a little sick, you get treated with a little bit of care,” said Kaplan. “You are really sick, you are receiving a lot of care. But if a COVID patient comes with hypertension, diabetes and obesity, we don’t say, “They have risk factors. Let’s put them in ICU.”

Liz Szabo writes for Kaiser Health News (KHN), a non-profit news service that covers health issues. It is an editorially independent program of Kaiser Family Foundation which is not affiliated with Kaiser Permanente.