Mounting evidence shows autoimmune responses play a significant role in long covid

Disease experts say it has become increasingly clear that an autoimmune response, in which antibodies attack the body’s own healthy cells and tissues, plays an important role in some cases of long-term Covid-19.

The latest evidence of this came in a study published last week in the European Respiratory Journal. It found that people with long-lasting Covid symptoms were more likely to have autoimmune disease markers in their blood than people who recovered quickly from the coronavirus or who had never contracted it.

Researchers took blood samples from 106 people who had contracted Covid three, six and 12 months after their diagnosis (although only 57 patients ended up taking part). They compared the samples to those from healthy people and people who had other types of respiratory infections at the start of the study.

After a year, 41% of the Covid group had detectable autoantibodies in their blood, while most healthy people had none. Autoantibody levels were also relatively low in the group with unrelated respiratory infections.

About 20% to 30% of the Covid group had markers of inflammation in their blood, as well as two specific types of autoantibodies with known links to autoimmune diseases. These patients typically experienced persistent fatigue and shortness of breath.

dr Manali Mukherjee, the study’s senior author and assistant professor of medicine at McMaster University, said her team plans to follow patients for up to two years after infection to see if their symptoms go away or if they develop diagnosable autoimmune diseases.

“There will be a subset of patients who will receive a lifetime diagnosis,” she said.

Mukherjee has a personal interest in the research: she contracted Covid a year and a half ago and still gets shortness of breath when she sings, swims or climbs stairs. Her symptoms also include headaches, fatigue, and brain fog.

The Centers for Disease Control and Prevention estimated in June that 1 in 13 US adults have long-term illness with Covid, defined as symptoms lasting three months or more.

“As we collect more data, I think the part of autoantibodies that is autoimmune will attract increasing suspicion and attention — and with good reason,” said E. John Wherry, an immunologist at the University of Pennsylvania who is not a graduate student Study involved research.

A March study of Covid patients found the presence of autoantibodies was linked to longer-lasting symptoms. At the start of the study, 6% of the patients had autoimmune diseases. But 44% of Covid patients who still had symptoms after two to three months had autoantibodies in their blood.

Another study found that compared to patients without autoantibodies, Covid patients with detectable autoantibodies had longer hospital stays and also had higher levels of persistent inflammation six months later.

dr Iñaki Sanz, head of the Department of Rheumatology at Emory University, estimates that 25% to 40% of patients with long-term Covid-19 disease have autoantibodies. These patients could benefit from the same types of anti-inflammatory drugs that are given to patients with lupus or rheumatoid arthritis, according to Sanz, who was not involved in the new study.

A large study led by University College London is currently recruiting people to study the effects of colchicine, an anti-inflammatory drug used to treat gout, on long Covid. Meanwhile, Resolve Therapeutics, a Florida-based biotechnology company, is enrolling participants in a Phase 2 trial of an experimental drug previously shown in a small study to curb the severity of lupus.

Researchers are still trying to determine whether Long Covid itself is an autoimmune disease, or whether Covid can trigger a secondary autoimmune disease, such as lupus or rheumatoid arthritis, for which some patients have been misdiagnosed.

Autoimmune diseases can be difficult to recognize because many have imprecise or overlapping definitions. There is no single test to diagnose lupus or rheumatoid arthritis.

Sanz said some patients with long-term Covid may have previously had autoantibodies in their blood, but “the infection may have made things more obvious or provided the last hit needed for autoimmunity to manifest.”

Wherry said the overall pace of research into treatments for long Covid was insufficient.

“Because we know so little about the disease, there’s been a certain reluctance to step up and try things,” he said.

Wherry is part of the newly formed Long Covid Research Initiative, a collective of scientists hoping to speed up the search for treatments. The initiative has received $15 million from the Balvi Scientific Investment Fund.

One area worth exploring is treatments that deplete or dysregulate B cells — white blood cells that produce antibodies — according to Wherry. These drugs are already being given to some cancer and multiple sclerosis patients. Wherry also pointed to a long-standing practice called plasmapheresis, in which the plasma (the liquid part of blood) is removed from patients in hopes of removing harmful antibodies as well.

Newer drugs “may be able to do this more efficiently and maybe even more specifically,” he said.

Of course, many long Covid patients have no signs of autoimmune disease, so this theory doesn’t explain all cases. The other prevailing hypothesis is that viruses or viral proteins that remain in the body continue to weaken the immune system.

If that’s the case, Sanz said, those patients could benefit from antivirals like Paxlovid. In one case study, a 47-year-old woman with Covid for six months saw her symptoms disappear a month after taking Paxlovid.

The two theories are not necessarily at odds, Wherry said: “We should consider that you could have a long Covid patient who has both viral persistence and autoantibodies.”

Mukherjee stressed that there is still hope for long Covid patients who have not yet recovered.

“If you’re in a phase where you’re three months, six months or eight months post Covid and you’re still not 100% healthy and you’re feeling tired and have this shortness of breath, just take care of yourself and maybe you’ll be better in the next 12, 13, 14 months,” she said.

Wherry predicted a renewed research focus on Long Covid as the US moves further away from the acute phase of the pandemic.

“Concern about dying from Covid is fading, which means we will be increasingly concerned about long-term Covid and chronic illness,” he said. “I think we’re right at the turning point.”