The Perfect Enemy | Mounting evidence shows autoimmune responses play a significant role in long Covid
February 29, 2024

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

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

The researchers took blood samples from 106 people who’d gotten Covid, at three, six and 12 months after their diagnosis (though by the end, only 57 patients were participating). They compared the samples to those from healthy people and people who’d had other types of respiratory infections at the beginning of the study.

After a year, 41% of the Covid group had detectable autoantibodies in their blood, whereas 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 particular types of autoantibodies with known links to autoimmune disease. Those patients tended to be the ones suffering from lingering fatigue and shortness of breath.

Dr. Manali Mukherjee, the study’s senior author and an assistant professor of medicine at McMaster University, said her team plans to follow up with the patients up to two years post-infection to see if their symptoms resolve or they develop diagnosable autoimmune diseases.

“There will be a subset of patients who will end up with a diagnosis for life,” she said.

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

The Centers for Disease Control and Prevention estimated in June that 1 in 13 U.S. adults have long Covid, defined as symptoms lasting three months or more.

“As we gain more data, I do think that the autoantibody, autoimmunity part of things is garnering increasing suspicion and attention — and for good reason,” said E. John Wherry, an immunologist at the University of Pennsylvania who was not involved in the research.

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

Another study found that Covid patients with detectable autoantibodies had prolonged hospitalization relative to those without autoantibodies, and also had higher levels of lingering inflammation six months later.

Dr. Iñaki Sanz, head of the rheumatology division at Emory University, estimated that 25% to 40% of long-Covid patients have autoantibodies. Those patients may benefit from the same types of anti-inflammatory drugs given to lupus or rheumatoid arthritis patients, according to Sanz, who was not involved in the new study.

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

Researchers are still trying to determine whether long Covid is itself an autoimmune condition or if Covid can trigger a secondary autoimmune disease like lupus or rheumatoid arthritis for which some patients haven’t been properly diagnosed.

Autoimmune diseases can be hard to detect, since many have loose or overlapping definitions. There’s no single test to diagnose lupus or rheumatoid arthritis.

Sanz said some long-Covid patients might have had autoantibodies in their blood before, but “the infection may have made things more obvious or may have provided the last hit that is required for autoimmunity to manifest.”

Wherry said that overall, the pace of research into treatments for long Covid has been insufficient.

“Since we know so little about the disease, there’s been some reluctance to go out on a limb and try things,” he said.

Wherry is a part of the newly formed Long Covid Research Initiative, a collective of scientists who hope to accelerate the search for treatments. The initiative has received $15 million from the scientific investment fund Balvi.

One area worth exploring, Wherry thinks, is treatments that deplete or dysregulate B cells — white blood cells that produce antibodies. These medications are already given to some cancer and multiple sclerosis patients. Wherry also pointed to a longstanding practice called plasmapheresis, which removes patients’ plasma (the liquid portion of blood) in hopes of also removing harmful antibodies.

Newer drugs “may be able to do that in a more efficient and perhaps even more specific way,” he said.

Of course, many long-Covid patients don’t have signs of an autoimmune disorder, so this theory doesn’t explain all cases. The other prevailing hypothesis is that lingering virus or viral proteins in the body continue to aggravate the immune system.

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

The two theories aren’t necessarily at odds, Wherry said: “We should keep in mind that you could have a long-Covid patient that both has viral persistence and also has autoantibodies.”

Mukherjee emphasized that there’s still hope for long-Covid patients who haven’t recovered yet.

“If you are at that phase where you’re three months, six months, or eight months post-Covid and you’re still not at 100% health, and you’re feeling fatigued and you have that shortness of breath, just take care of yourself and maybe within the next 12, 13, 14 months, you’ll possibly get better,” she said.

Wherry predicted a renewed research focus on long Covid as the U.S. continues to move away from the acute phase of the pandemic.

“The concern about dying from Covid is going away, which means that we’re going to have increasing concern about long Covid and chronic diseases,” he said. “I think we’re right at the inflection point.”