Friendly Fire | “Breaking Discovery” May Show Why Certain COVID-19 Patients Die

Dr. Megan Lanny has learned a lot about COVID-19 since he began treating patients with this disease in the emergency department in February.

But there is one question she still can’t answer: what makes her so sick than other patients?

Increasing age and the underlying medical problems explain only part of the phenomenon, Ranny said, who saw patients of similar age, background, and health follow very different trajectories.

“Why does a 40-year-old really get sick and another doesn’t even have to be hospitalized?” Asked Lanny, an associate professor of emergency medicine at Brown University.

In some cases, provocative new research shows. Some people, especially men, succumb because their immune system has been hit by friendly fire. Researchers hope that this finding will help develop targeted therapies for these patients.

In an international study of science, about 10% of about 1,000 COVID-19 patients who developed life-threatening pneumonia had antibodies that abolished a major immune system protein called interferon. These antibodies (known as autoantibodies because they attack the body itself) were not found at all in 663 people with mild or asymptomatic COVID-19 infection. Only 4 out of 1,227 healthy individuals had autoantibodies. Published on October 23, the study was led by 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 pandemic began,” said Dr. Eric Topol, Executive Vice President of Research at Scripps Research in San Diego. Survey. “This is a breakthrough discovery.”

In a second scientific study by the same team, the authors found that an additional 3.5% of critically ill patients had mutations in genes that control interferon, which is involved in the fight against the virus. Given that the body has 500 to 600 of these genes, researchers may find more mutations, said Qian Zhang, the lead author of the second study.

Interferon acts as the body’s first line of defense against infection, sounds a warning, activates an army of genes that fight the virus, and is a deputy research scientist at the Center for Infectious Immunity at Columbia University’s Merman School of Public Health. Said scholar Angela Rasmussen.

“Interferon is like a combination of a fire alarm and a sprinkler system,” said Rasmussen, who was not involved in the new research.

In some people with COVID-19, interferon is probably suppressed by the virus itself, according to laboratory studies.

Interferon is especially important for protecting the body from new viruses such as the coronavirus that the body has never encountered, said Chan, a researcher at the St. Giles Infectious Diseases Genetics Institute at Rockefeller University. It was.

“Your body should sound an alarm everywhere,” Zhang said when infected with the new coronavirus. “If the alarm doesn’t sound, there can be a lot of viruses everywhere.”

Importantly, the patient did not make autoantibodies in response to the virus. Instead, they seemed to have them before the pandemic began, said Paul Busterd, the lead author of antibody research and a researcher at Rockefeller University.

Autoantibodies did not cause problems until the patient was infected with COVID-19 for reasons the researchers did not understand, Bastard said. For some reason, the new coronavirus, or the immune response it caused, seems to have driven them.

“Before COVID, their condition was silent,” Bastard said. “Most of them have never been ill before.”

Bastard said he suspects that autoantibodies to interferon may also increase the risk of other viruses such as influenza. “Some of the patients who participated in his study have had the flu in the past. We are investigating whether autoantibodies may have affected the flu.”

Sabrakline, a professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School, has evolved the way viruses and the immune system compete in a sort of armed competition, evading the immune system and suppressing its response. Scientists have long known that they are. Of public health.

Antibodies are usually heroes of the immune system and protect the body from viruses and other threats. However, a phenomenon known as an autoimmune disease can cause the immune system to appear disrupted and produce autoantibodies. It occurs in diseases such as rheumatoid arthritis, in which antibodies attack the joints, and type 1 diabetes, in which the immune system attacks insulin-producing cells in the pancreas.

Doctors do not know the exact cause of the autoimmune disease, but observe that symptoms often occur after a viral infection. Autoimmune diseases become more common as we get older.

Yet another unexpected finding was that 94% of patients in studies using these autoantibodies were male. About 12.5% ​​of men with life-threatening COVID-19 pneumonia had autoantibodies to interferon, compared to 2.6% of women.

This was unexpected, according to Klein, given that autoimmune diseases are much more common in women.

“I’ve been studying gender differences in viral infections for 22 years, but no one studying autoantibodies thought it would be a risk factor for COVID-19,” Klein said. I will.

The study may help explain why men are more likely to be ill and die of COVID-19 than women, Klein said.

“The number of men dying in their thirties, not just those in their eighties, is increasing significantly,” she said.

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

Women have two copies of this chromosome — along with two copies of each gene. According to Iwasaki, she will provide backups to women in case one copy of the gene is defective.

However, men have only one copy of the X chromosome. Therefore, if there is a defect or harmful gene on the X chromosome, there is no other copy of that gene to fix the problem, Iwasaki said.

Bastard said one woman in the study that developed the autoantibodies had a rare genetic condition with only one X chromosome.

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

Researchers quickly realized that Spanish men were also more likely to die from COVID-19, but Spanish men and women smoke at about the same rate, Klein said.

Experts hypothesize that men are less likely to wear masks in public than women and are more likely to delay seeking medical care, which may increase their risk. He said.

But the differences in behavior between men and women are only part of the answer. Scientists say that while the hormone estrogen can somehow protect women, testosterone can put men at greater risk. Interestingly, recent studies have shown that obesity poses a much greater risk to men with COVID-19 than to women.

Still, women have their own form of suffering from COVID-19.

Studies show that women are four times more likely to experience long-term COVID-19 symptoms that last from weeks to months, such as fatigue, weakness, and a form of confusion known as “brain fog.” Is shown.

As a woman, “maybe we will survive it and are unlikely to die, but then we have all these long-term complications,” she said.

After reading the study, Klein said he wanted to know if patients who became severely ill with other viruses, such as the flu, also contained genes and antibodies that disabled interferon.

“There is no evidence of this in the flu,” Klein said. “But we haven’t investigated. Through COVID-19, we may have discovered a very new disease mechanism that has been found to be present in many diseases.”

Indeed, scientists say the new study solves only part of the mystery of why patient outcomes can change so much.

Researchers say that some patients may be protected by past exposures to other coronaviruses. Patients who are very ill may have inhaled high doses of the virus, such as due to repeated exposure to infected colleagues.

Doctors have been looking for a link between illness results and blood type, but studies have produced conflicting results.

Busterd, who belongs to the Necker Children’s Hospital in Paris, said screening patients for autoantibodies to interferon could help predict which patients are very likely to get sick. Stated. The test takes about 2 days. He said hospitals in Paris can now screen patients on demand from doctors.

Only 10% of life-threatening patients with COVID-19 have autoantibodies, but “I think everyone in the hospital should be tested,” Bastard said. Otherwise, “I don’t know who is at risk for the severe form of the disease.”

Bastard said he hopes his findings will lead to new life-saving therapies. He states that the body produces many types of interferon. Giving these patients different types of interferon (those not disabled by genes or autoantibodies) may help them fight the virus.

In fact, a pilot study of 98 patients published in the Lancet Respiratory Medicine Journal on Thursday showed the benefits of inhaled interferon. In an industry-funded UK study, hospitalized COVID-19 patients randomly assigned to receive interferon beta-1a are more than twice as likely to recover enough to resume normal activity as other patients. was.

Researchers need to confirm these findings in a much larger study, said Dr. Nathan Peifers Maja, a researcher at Imperial College London, who was not involved in the study but wrote an accompanying editorial. Stated. Future studies will need to test patients for genetic mutations in their blood and autoantibodies to interferon to see if they respond differently than other patients.

Peiffer-Smadja states that inhaled interferon may be more effective than the injected form of the drug because it is delivered directly to the lungs. The injectable version of interferon has been used for years to treat other illnesses, but the inhaled version is still and not commercially available.

And a study led by the World Health Organization found that the drug injected into COVID-19 patients had no benefit, so doctors need to be aware of interferon for now, Peiffer said. -Smadja said. In fact, patients who received interferon tended to have higher mortality rates, but this finding may have been a coincidence. Administration of interferon later in the disease may promote a destructive immune hyperreactivity called a cytokine storm. In this case, the immune system does more damage than the virus.

According to clinicaltrials.gov, a database of research studies at the National Institutes of Health, scientists worldwide have launched more than 100 clinical trials of interferon.

Until a larger study is completed, doctors say that the discovery of Bastard is unlikely to change the way COVID-19 is treated.

Dr. Luis Kaplan, president of the Society of Emergency Medicine, said patients would be treated according to their symptoms rather than risk factors.

“If you are a little sick, you will be treated with a little care,” Kaplan said. “You are really sick and get a lot of care, but if COVID patients have high blood pressure, diabetes, or obesity, they don’t say,” They have risk factors. Let’s get into the ICU. ” .. “