Covid-19 Is Looking More and More Like an Autoimmune Disease
By: Markham Heid
Tags: Pandemic, Covid 19, The Nuance, Body, Coronavirus

Covid-19 Is Looking More and More Like an Autoimmune Disease

Autoimmunity may explain how the virus inflicts such widespread and unpredictable damage

Throughout the pandemic, doctors have noticed a confounding phenomenon: A lot of people infected by the coronavirus develop myocarditis, an inflammation of the heart that can cause lasting damage and death.

Even among people who have mild Covid-19 or who are asymptomatic, experts have found evidence of heart inflammation. A July study published in JAMA Cardiology found that 60% of coronavirus patients had active myocarditis two months after their initial infection. Remarkably, the study found that this inflammation was as common among people who recovered at home as it was among those who required hospitalization. (Myocarditis can often go undetected; its symptoms can be subtle and include shortness of breath, chest pain, and a fluttering heart.)

“We’re still questioning why we see this inflammation in the heart,” says John Swartzberg, MD, an emeritus professor of infectious diseases and vaccinology at the UC Berkeley School of Public Health. “One of the hypotheses is that there’s an autoimmune process at work.”

“It seems that Covid-19 shares a similar inflammatory immune response with autoinflammatory and autoimmune conditions.”

“Autoimmunity” describes immune system activity — primarily inflammation — that is directed at healthy cells, tissues, or other inappropriate targets in the body. Autoimmune diseases, such as lupus and multiple sclerosis, are defined by this inappropriate inflammation and its resulting damage. When it comes to Covid-19 and myocarditis, Swartzberg says the autoimmune hypothesis posits that SARS-CoV-2 causes the immune system to misidentify something in the heart’s cells as dangerous. This misidentification leads to inflammation.

He’s quick to add that this theory is just one of several possible explanations. The presence of inflammation, even if it lingers after the virus is wiped out, is not by itself an indicator of autoimmune disease, he says.

But other researchers have made the case that Covid-19 is often driven by autoimmune processes. “It seems that Covid-19 shares a similar inflammatory immune response with autoinflammatory and autoimmune conditions,” write the authors of a recent study in the Journal of Immunology. They lay out evidence that SARS-CoV-2 may cause the body’s immune system to mistakenly attack its own cells and tissues — in the heart, in the brain, and elsewhere.

Autoimmunity, they suggest, may explain how the virus inflicts such widespread and unpredictable damage. Understanding these autoimmune processes may be the key to preventing that damage and saving lives.

The case for autoimmune involvement

In October, a study in Nature Immunology examined the activity of immune cells and antibodies among people with severe Covid-19. It found some striking resemblances to autoimmune disease.

“We observed the same type of B-cell activity we see in lupus flares, and also similar antibody activity,” says Ignacio Sanz, MD, co-author of the study and director of the Lowance Center for Human Immunology at Emory University. Sanz has also examined the immune systems of people with mild or persistent (aka long-haul) Covid-19; there again, he sees overlap with autoimmune conditions.

Sanz says it’s possible that the phenomena he has documented are simply indicators of an aggressive immune response to an invading virus. But he says that in at least a subset of patients, elements of autoimmunity are strongly implicated in the development of severe Covid-19.

How could the coronavirus cause a person’s immune system to mistakenly attack its own cells and tissues? Part of it may have to do with what biologists call molecular mimicry.

“There are a number of similarities between the amino acid sequences of [coronavirus] proteins and those of human proteins,” says Timothy Icenogle, MD, a cardiothoracic surgeon and author of a recent paper on the autoimmunity elements of Covid-19, published in Frontiers in Immunology. These protein similarities may confuse the immune system and cause it to attack its own healthy cells; in some people, this attack may continue even after the true virus cells have been wiped out.

Autoimmunity could explain why a robust immune response to the virus — one that includes the production of coronavirus-neutralizing antibodies — does not always correlate with mild Covid-19. It may be that in some patients, an immune response intended to eliminate the virus ends up also attacking healthy cells. These autoimmune phenomena could also explain why myocarditis and other forms of inflammation or injury show up weeks or months after a person has ostensibly recovered from a coronavirus infection.

“We’re gradually coming to the realization that Covid-19 is primarily an autoimmune disease that is triggered by a virus.”

How old weapons could fight a new virus

Icenogle is a cardiac surgeon. “So I’m about the last doctor you’d expect to be writing a paper on Covid-19,” he says. But he spent 25 years as director of a heart transplant program, which provided him with a good understanding of immunology — something he says is uncommon for cardiologists.

During the years he was running the transplant program, Icenogle occasionally encountered cases of viral myocarditis, which before the pandemic was a rare and often deadly condition. This led him to some surprising insights. “When we looked at the postmortem heart specimens from these myocarditis patients, it looked like they’d died of cardiac rejection,” he says. “We thought, gee whiz, how could this be? How could a virus cause you to reject your own heart like it was a transplant?”

Icenogle combed the research and found evidence that autoimmune processes — ones triggered by a virus — could be to blame. He later had success treating myocarditis with powerful transplant drugs that essentially turned off the immune system and therefore blocked the autoimmune processes from doing more damage.

Now, in the context of the pandemic, Icenogle speculates that some of these same transplant drugs may prove helpful in treating Covid-19. He mentions one in particular, rabbit antithymocyte globulin (rATG), which he has used to save the lives of some people with viral myocarditis. Not only does rATG calm the immune system, Icenogle says, but it also helps limit blood coagulation, which is another feature of severe and deadly Covid-19.

So far, there is no published research on rATG or similar heavy-duty transplant drugs for the treatment of Covid-19. “These are very powerful drugs, and there’s a risk you might endanger someone,” Icenogle says. Some doctors have been willing to test out comparatively mild immunosuppressant drugs, and at least one of those—dexamethasone—has worked. But Icenogle says that many in medicine regard the notion of depleting the immune system of a virus-stricken patient as “at least paradoxical, if not crazy.”

He thinks that will change. “We’re gradually coming to the realization that Covid-19 is primarily an autoimmune disease that is triggered by a virus,” Icenogle says. “I submit that eventually we’re going to treat these autoimmune processes with some of our big guns.”

Emory University’s Sanz says he also believes that immune-suppressing drugs, including some that have not yet been tried in people with Covid-19, will prove helpful. “Without any doubt,” he says. “But I think that only some patients will benefit.”

He emphasizes, again and again, that Covid-19 is a heterogeneous disease. It affects different people in different ways. Outside of a vaccine, there is unlikely to be a panacea or a single category of treatment that works for everyone. Still, Sanz says that a better understanding of the disease’s autoimmune facets, coupled with a broader deployment of immune-moderating therapies, could help improve patient outcomes — both in the short and long term.

“I think autoimmunity is part of the story,” Sanz adds. “It’s not the whole story.”