Megan Ranney’s Quest to Understand COVID-19 Severity Differences
Megan Ranney has learned a lot about COVID-19 since she started 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 sicker than others?
Age and underlying medical problems only partially explain the phenomenon, said Ranney, who has seen patients of similar age, history, and health status follow completely different trajectories.
“Why does one 40-year-old get very sick and another doesn’t even need to be hospitalized?” asked Ranney, an associate professor of emergency medicine at Brown University.
In some cases, provocative new research shows that certain individuals – particularly men – succumb because their immune systems are hit by friendly fire. Researchers hope this discovery will help them develop targeted therapies for these patients.
In an international study published in Science, 10% of nearly 1,000 COVID patients who developed life-threatening pneumonia had antibodies that deactivate key immune system proteins called interferons. These antibodies – known as autoantibodies because they attack the body itself – were not found in 663 people with mild or asymptomatic COVID infections. Only four out of 1,227 healthy individuals had the autoantibodies. The study, published on October 23, 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 beginning 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 by the same team, the authors found that an additional 3.5% of critically ill patients had mutations in genes that control interferons involved in fighting viruses. Since the body has 500 to 600 of these genes, researchers may find more mutations, said Qian Zhang, the 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 researcher 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 was not involved in the new studies.
Laboratory studies show that interferons are suppressed in some people with COVID-19, perhaps by the virus itself.
Interferons are particularly important in protecting the body against new viruses like the coronavirus, which the body has never encountered before, said Zhang, a researcher at the St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller University.
When infected with the new coronavirus, “your body should have alarms going off everywhere,” Zhang said. “If you don’t sound the alarm, you can have viruses all over the place in large numbers.”
Significantly, the patients did not develop autoantibodies in response to the virus. Instead, they appeared to have acquired them even before the pandemic began, said Paul Bastard, the lead author of the antibody study, also a researcher at Rockefeller University.
For reasons that researchers don’t understand, the autoantibodies never caused problems until the patients were infected with COVID-19, Bastard said. Somehow, the new coronavirus, or the immune response it triggered, seems to have set them in motion.
“Before COVID, their condition was silent,” Bastard said. “Most of them hadn’t been sick before.”
Bastard said he now wonders if autoantibodies against interferons also increase the risk of other viruses, such as the flu. Among the patients in his study, “some of them had had the flu in the past, and we are looking to see if the autoantibodies could have had an effect on the flu.”
Scientists have long known that viruses and the immune system compete in a kind of arms race, with viruses developing ways to evade the immune system and even suppress its response, said Sabra Klein, a 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 against viruses and other threats. But sometimes, in a phenomenon known as autoimmune disease, the immune system seems confused and creates autoantibodies. This happens in diseases like rheumatoid arthritis, where antibodies attack the joints, and in type 1 diabetes, where the immune system attacks insulin-producing cells in the pancreas.
While doctors don’t know the exact causes of autoimmune diseases, they have observed that the conditions often occur after a viral infection. Autoimmune diseases are more common with aging.
In another unexpected finding, 94% of patients in the study with these autoantibodies were men. About 12.5% of men with life-threatening COVID pneumonia had autoantibodies against interferons, compared to 2.6% of women.
This was unexpected, as autoimmune diseases are much more common in women, Klein said.
“I’ve been studying sex differences in viral infections for 22 years, and I don’t think anyone studying autoantibodies thought this would be a risk factor for COVID-19,” Klein said.
The study may help explain why men are more likely than women to become severely ill with COVID-19 and die, Klein said.
“You see significantly more men dying in their 30s, not just in their 80s,” she 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. This gives women a backup in case one copy of a gene becomes defective, Iwasaki said.
Men, however, have only one copy of the X chromosome. So, if there is a defect or a harmful gene on the X chromosome, they won’t have another copy of that gene to fix the problem, Iwasaki said.
Bastard noted that a woman in the study who developed autoantibodies has a rare genetic condition where she has only one X chromosome.
Scientists have struggled to explain why men are at 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 were much more likely to smoke than Chinese women.
Researchers quickly noticed that men in Spain were also more likely to die from COVID-19, even though men and women there smoke roughly in the same proportions, Klein said.
Experts hypothesized that men may be at higher risk because they are less likely to wear masks in public than women and more likely to delay seeking medical care, Klein said.
But behavior differences between men and women only provide 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 poses a much greater risk for men with COVID-19 than for women, Klein said.
However, women have their own way of suffering from COVID-19.
Studies show that women are four times more likely to experience long-term COVID symptoms, lasting weeks or months, including fatigue, weakness, and a type of mental confusion known as “brain fog,” Klein noted.
As women, “maybe we survive and are less likely to die, but then we have all these long-term complications,” she said.
After reading the studies, Klein said she wonders if patients who become critically ill with other viruses, such as the flu, also have genes or antibodies that deactivate interferon.
“There’s no evidence of that in the flu,” Klein said. “But we didn’t look. Through COVID-19, we may have discovered a very new disease mechanism, which we may find is present in various diseases.”
To be sure, scientists say the new study only solves part of the mystery of why patients’ outcomes can vary so much.
Researchers say it’s possible that some patients are protected by previous exposure to other coronaviruses. Patients who become very ill may have also inhaled higher doses of the virus, such as through repeated exposure to infected coworkers.
While doctors have sought links between disease outcomes and blood type, the studies have produced conflicting results.
Screening for interferon autoantibodies in patients may help predict which patients are more likely to get sick, said Bastard, who is also affiliated with Necker Hospital for Sick Children in Paris. The test takes about two days. Hospitals in Paris can now screen patients at the request of a physician, he said.
While only 10% of life-threatening COVID-19 patients have autoantibodies, “I think we should apply the test to everyone who’s hospitalized,” Bastard said. Otherwise, “we wouldn’t know who’s at risk of getting a severe form of the disease.”
Bastard said he hopes his findings will lead to new life-saving therapies. He notes that the body produces many types of interferons. Giving these patients a different type of interferon – one that isn’t disabled by their genes or autoantibodies – may help them fight the virus.
Indeed, a pilot study of 98 patients published on Thursday in The Lancet Respiratory Medicine found benefits from an inhaled form of interferon. In the industry-funded British study, COVID-hospitalized patients randomly assigned to receive interferon beta-1a were more than twice as likely to recover enough to resume their regular 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 study but wrote an accompanying editorial. Future studies should test patients’ blood for genetic mutations and autoantibodies against interferon, to see if they respond differently from others.
Peiffer-Smadja notes that inhaled interferon may work better than an injected form of the drug because it is delivered directly to the lungs. While injected versions of interferon have been used for years to treat other diseases, the inhaled version is still experimental and not commercially available.
And doctors should be cautious with interferon for now, because a study led by the World Health Organization found no benefit to an injected form of the drug in COVID patients, Peiffer-Smadja said. In fact, there was a trend toward higher mortality rates in patients who received interferon, although that finding may be due to chance. Administering interferon later in the course of the disease may stimulate a destructive immune reaction called cytokine storm, in which the immune system causes more damage than the virus.
Worldwide, scientists have launched over 100 interferon clinical trials, according to clinictrials.gov, a National Institutes of Health research database.
Until larger studies are completed, doctors say Bastard’s findings are unlikely to change how 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 bit sick, you get a little bit of care,” Kaplan said. “You’re very sick, you get a lot of care. But if a COVID patient comes in with hypertension, diabetes, and obesity, we don’t say, ‘They have risk factors. Let’s put them in the ICU.'”