How Viral Infections Cause Long-Term Health Problems

Every day, Davida Wynn sets herself one task: Take a bath. Or wash the dishes. Or make an elaborate meal. By the end of the chore, she is exhausted and has to sit or lie down, sometimes falling asleep wherever she happens to be.

“Anything beyond that is truly excruciating,” Ms. Wynn, 42, said.

Her heart races even during small tasks, and she often gets dizzy. At least once a month, she falls at her home outside Atlanta. Once she badly bruised her face, and another time she banged up her knee.

Ms. Wynn was infected with the coronavirus in May 2020, when she was a nurse in a hospital Covid unit, and became so ill she was put into a medically induced coma for six weeks. Ever since, her bloodwork has indicated that she is experiencing extreme inflammation, a hallmark of autoimmune disease.

Infection with the coronavirus is known to leave behind a long legacy of health problems, many of which are characterized as long Covid. But mounting evidence suggests that independent of that syndrome, the coronavirus also befuddles the immune system into targeting the body, causing autoimmune disorders in some people.

This outcome is more likely in those who, like Ms. Wynn, were severely ill with Covid, multiple studies suggest.

Covid is not unique in this aspect. Scientists have long known that infection can set the body down the path of autoimmune disease. The classic example is Epstein-Barr virus.

About one in 10 people who have mononucleosis, which is caused by the virus, go on to develop myalgic encephalomyelitis/chronic fatigue syndrome. A landmark study last year even linked the virus to multiple sclerosis.

Many other pathogens can also seed autoimmunity — but only in an unlucky few people.

“We are all infected with a multitude of viruses, and in the majority of cases, we don’t get any autoimmunity,” said Dr. Alberto Ascherio, an epidemiologist at the Harvard T.H. Chan School of Public Health who led the multiple sclerosis study.

Infections with bacteria such as chlamydia and salmonella can inflame the joints, skin and eyes — a condition called reactive arthritis. Enteroviruses can mislead the body into attacking its own pancreatic cells, leading to Type 1 diabetes.

Like Epstein-Barr virus, dengue and H.I.V. are thought to cause autoimmunity in some people. Still, Covid seems to foment a long-term reaction that is distinct, said Dr. Timothy Henrich, a virologist at the University of California, San Francisco.

“There’s something specific about SARS-CoV-2 that seems to set it apart, in terms of the severity and duration,” he said, referring to the coronavirus.

Early in the pandemic, scientists found that antibodies that target the body instead of the pathogen — so-called autoantibodies — are important in Covid. Those who had autoantibodies to interferon, a key component of the body’s first-response system to pathogens, before they encountered the coronavirus were more likely to fare poorly or to die of Covid.

About 10 percent of patients with severe Covid, most of them men over age 55, had these antibodies, compared with just 0.3 percent in the general population.

Since then, dozens of studies have found autoantibodies in people who have had Covid. Up to half of people who have had the illness carry antibodies that can alter the immune system, damage blood vessels, impair blood pressure regulation and lead to diabetes, rheumatoid arthritis and blood clots.

One study found autoantibodies in children with multisystem inflammatory syndrome, a rare condition associated with Covid.

The autoantibodies seem to be independent of long Covid. A few studies have linked a subset of autoantibodies to long Covid, and found that their presence is one of four major risk factors for the syndrome.

But other teams have reported that the autoantibodies and long Covid don’t always accompany each other. Based on an analysis of thousands of proteins, “this autoantibody signature seems to be a Covid-related phenomenon, post-Covid and not long Covid-related,” Dr. Henrich said.

But some researchers caution that the mere presence of autoantibodies does not herald autoimmune disease.

“In every viral infection, you get autoantibodies, and this has been known for decades,” said Dr. Shiv Pillai, an immunologist at Harvard Medical School.

Many years from now, scientists may record a higher incidence of autoimmune diseases in those who had severe Covid, he said, but that is not a foregone conclusion: “There may be many, many other factors that have to be fulfilled for someone to get the disease.”

Why only some people develop autoimmune conditions is unclear, but the answer is likely to involve dozens of genes and an environmental catalyst.

Lupus is preceded by high levels of autoantibodies more than 10 years before disease onset, but many relatives of patients with lupus who have a similar genetic background never develop the disease.

“The most likely explanation is that you have all these risk factors, you have all these things ready to go, and there’s a final trigger,” said Dr. Iñaki Sanz, an immunologist at Emory University.

To conclusively link a virus to an autoimmune condition, rigorous studies would need to follow a large number of people over many years. The best example of such a study is the one that tied the Epstein-Barr virus to multiple sclerosis.

E.B.V., a member of the herpesvirus family, infects nearly everyone at some point. Once in the body, it persists forever; the virus can be reactivated by conditions including stress and hormonal changes. (Reactivation of E.B.V. is another of the four risk factors for long Covid.)

To probe its association with multiple sclerosis, Dr. Ascherio and his colleagues conducted what they call an “experiment of nature” — a long-term study of more than 10 million active-duty soldiers in the U.S. military.

Between 1993 and 2013, the researchers collected 62 million serum samples from this racially diverse group. Those who were infected with E.B.V. had a 32-fold increase in the risk of multiple sclerosis, compared with those who did not have the virus, the scientists found. They did not observe similar relationships with other viruses.

Fewer than one million Americans have multiple sclerosis, suggesting that other factors must also be involved. Still, researchers are now enthusiastic about the idea of a vaccine against E.B.V. to prevent multiple sclerosis. (No vaccines against E.B.V. are currently available, although some are in clinical trials.)

Studies from other teams support the association between E.B.V. and multiple sclerosis. Danish researchers followed more than 25,000 people with mononucleosis over decades and found that it doubled their odds of developing multiple sclerosis.

And a study published last year offered a possible explanation: E.B.V. mimics a human protein, potentially misdirecting antibodies made against the virus.

About one in four people with multiple sclerosis has these antibodies, “providing the basis for how E.B.V. could evoke an autoimmune reaction that would cause multiple sclerosis,” said Dr. William Robinson, an expert in autoimmune diseases at Stanford University who led the study.

This sort of molecular mimicry is one path to autoimmunity. But in other cases, the body may never fully clear a pathogen after infection, and the persistence of the virus — whether live virus or just remnants — may keep the body in a state of immune high alert, eventually leading to autoimmunity.

Both possibilities suggest treatments. In some small number of people, antiviral drugs and vaccination can ease the symptoms of long Covid, hinting that live virus may be the source. Dr. Henrich is conducting a study looking at monoclonal antibodies at high doses that would soak up errant viral fragments lingering in the body.

“If the viral proteins are causing an auto-reactive process, then by getting rid of those viral proteins, it might actually improve overall health,” Dr. Henrich said.

For Ms. Wynn, there is no relief in sight. She has tried a plethora of medications, including treatments for rheumatoid arthritis, but so far has not responded to them.

“It’s been a long and tedious process,” Ms. Wynn said. “And I will tell you, from a mental perspective, it has been absolutely draining.”