Why Do POTS and Long Covid Look So Much Like Autoimmune Disorders?

In 2002, Sarah Schafer, a physician based in the San Francisco area, began to develop a strange set of symptoms: lightheadedness, headaches, joint pains, brain fog, and extreme fatigue. Standing for more than five minutes was almost impossible.

After seven years of being confined to bed for most of the day, Schafer was eventually diagnosed with postural orthostatic tachycardia syndrome, or POTS for short, a disorder of the autonomic nervous system, a network of nerves throughout the body that control involuntary processes, such as heart rate, breathing, and digestion.

But Schafer was also diagnosed with Sjögren’s disease, a systemic autoimmune disorder typically characterized by symptoms such as dry eye and dry mouth—although patients report that symptoms are much more widespread and complicated than that. And as it turned out for Schafer, the POTS symptoms had been an early warning sign of her autoimmune disease.

(What is POTS? This strange disorder has doubled since the pandemic.)

Experts are starting to recognize that autonomic nervous system dysfunction, or dysautonomia, can be a significant part of autoimmune diseases like Sjögren’s. Indeed, research has shown that people with POTS have a much higher chance of being diagnosed with autoimmune diseases, such as lupus or Hashimoto’s, either before or after their POTS symptoms develop, with studies suggesting that’s true for one out of every five people with POTS. Even if they don’t have a formal diagnosis, people with POTS are also more likely to have other autoimmune markers.

Conversely, research shows that people with autoimmune disorders also have a high probability of developing some sort of nervous system dysfunction, such as POTS. This link extends to people with disorders that are similar to POTS, such as long COVID or myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). All three are known as infection-associated chronic conditions, which are triggered by some sort of insult to the immune system, such as a viral infection, pregnancy, or a major injury, such as a concussion or surgery.

Blair Grubb, a cardiologist at the University of Toledo Health who has been treating POTS patients for almost 40 years, has found that many of his patients report a specific trigger for their illness, which he calls an “index event.” Many of those same triggers are also known for triggering autoimmune disorders. “I started saying, this sounds like an autoimmune disorder,” Grubb says.

It’s unlikely that POTS and its brethren will ever be classified as autoimmune disorders themselves—they look too different from one patient to another, which suggests they’re driven by a number of disruptions in the body. But understanding why they look so much like an autoimmune disorder could be a huge step forward for science—and for finding lasting treatments.

There are two prevailing theories as to how and why autoimmune diseases develop. The first is called molecular mimicry, in which proteins from a pathogen, such as a virus, look similar to a protein in the body. This can lead the immune system to attack the body in pursuit of the pathogen.

The second theory is that chronic inflammation can degrade tissues within the body, which then releases a cascade of proteins and molecules that the body recognizes as abnormal. This can cause the body to turn against itself, with the immune system attacking these proteins as a foreign invader. “It starts to make antibodies against itself,” says Ilene Ruhoy, a neurologist and medical director for the Chiari/EDS Center at Mount Sinai South Nassau.

(Why women are more prone to autoimmune diseases.)

In both scenarios, the immune system makes antibodies that attack the body, which are called auto-antibodies. Which type of autoimmune disease you get depends on which auto-antibodies are made, and which parts of the body they attack.

Many experts now believe that dysfunction of the autonomic nervous system is related. 

The autonomic nervous system can be thought of as the check engine light of the body, blaring a warning whenever something in the body is amiss, says Brent Goodman, a neurologist at HonorHealth. When the autonomic nervous system detects a revved-up immune system, it revs up too.

“Once the immune system is dysregulated, you just have this consistent immune provocation, that creates this sort of chronic, systemic inflammatory response, which then ultimately affects and intersects with the nervous system,” Ruhoy says.

Over time, all this activity begins to “chew” away at the autonomic nervous system, fraying the delicate nerves that run throughout the entire body and are responsible for telling various organs, such as the heart or the digestive system, what to do.

These frayed and inflamed nerves are no longer able to effectively send messages between the organs and the brain. So when the heart and blood vessels fail to move blood through the body efficiently, it can lead to lightheadedness and a racing heart characteristic of conditions like POTS. When the gastrointestinal system can’t digest food properly, it can likewise cause symptoms like chronic diarrhea or constipation.

The relationship is also a two-way street—an autonomic nervous system in overdrive can also send the immune system into disarray. “We’re now seeing themes across multiple diseases, including long COVID, ME/CFS, POTS,” where a viral infection will activate the immune system and potentially cause autoimmune diseases, says PJ Utz, a researcher at Stanford University.

Scientists are increasingly realizing that they can use the same tactic to understand the causes of POTS and other autonomic nervous system conditions as they do for autoimmune diseases.

Both types of disease develop when antibodies attack the body instead of helping it, leading to damage within the organs or tissues that are being targeted. So figuring out which specific auto-antibodies are causing the damage is the key to understanding them, says Neils Eijkelkamp, a researcher at University Medical Center Utrecht, in the Netherlands.

Take a pair of recent long COVID studies, for instance. Eijkelkamp and his collaborators recently studied immunoglobulin G, a type of antibody stored in your body after you’ve cleared an infection, in people with long COVID. They found that infusing these auto-antibodies into mice led to the development of neurological symptoms that are associated with chronic pain.

(Why long COVID can destroy your ability to exercise.)

In a similar experiment, Yale University researcher Akiko Iwasaki and her collaborators infused auto-antibodies from people with long COVID into mice, which led the animals to develop neurological symptoms, such as fatigue, issues with balance and coordination, nerve damage, and chronic pain.

Both studies provide a potential link between the presence of auto-antibodies in people with long COVID and the development of neurological symptoms—a sign that these specific auto-antibodies attack the nervous system.

A number of studies have also found auto-antibodies in people with POTS, including those that attack the body’s adrenergic receptors, which control the body’s “fight-or-flight” response, and muscarinic receptors, which control the body’s “rest-and-digest” response. Disrupting these receptors would theoretically impair the autonomic nervous system’s ability to regulate these responses, however, researchers have not yet been able to prove these auto-antibodies are causing the onset of POTS symptoms.

But once you identify the auto-antibodies that are responsible for a disease, as Eijkelkamp and his team is now attempting to do for long COVID, you can target them.

Experts are hopeful that teasing out the strong link between immune system dysregulation and autonomic nervous system dysfunction will also open up potential new avenues for treatment.

For instance, autoimmune disorders such as lupus or Sjögren’s are sometimes treated with intravenous immunoglobulin, an injection of antibodies from healthy donors that are thought to help counteract whatever is going haywire in the immune system. The National Institutes of Health is currently testing whether this therapy could also be used as a potential treatment for people with long COVID.

Meanwhile, experts are calling for the development of clinical trials to test a wide range of immunotherapies, including intravenous immunoglobulin as well as plasma exchange and biologic drugs, for people with POTS and long COVID since these treatments are known to target the type of immune system dysfunction associated with these conditions.

Although these therapies show promise, Ruhoy says there are some drawbacks. Many of her patients with POTS, ME/CFS, and long COVID do respond to immunotherapies—but not for long.

“It’s not really getting to the core root of the disease, which is why eventually the disease process itself overwhelms the medication that we’re using as an intervention, and then the symptoms start to recur,” Ruhoy says.

Beyond repurposing treatments intended for autoimmune disorders, she says, there is more work that needs to be done to figure out the exact pathways that lead to dysautonomic conditions like POTS—and to devise tailored treatments that may finally offer relief to patients like Schafer.