A Long-Ignored Syndrome Is Drawing Unprecedented Attention

Three months after a SARS-CoV-2 infection wrecked her Thanksgiving break, 19-year-old college student Hannah Harding was attending a lecture when she started shaking and sweating profusely. She glanced at her Apple watch: Her heart rate was 140 beats/min.She felt exhausted and became easily winded over the next few days. “What was usually a 15-minute walk to class ended up being a half hour because I would have to fully stop and sit on the curb,” said Harding, now 24, a film production assistant from Maplewood, New Jersey. She also had brain fog and no appetite.While home on spring break, she finally got a diagnosis: postural orthostatic tachycardia syndrome (POTS), a disorder of the autonomic nervous system that has become exponentially more common since the pandemic, with its incidence increasing by an estimated two- to fivefold, especially in young women. POTS causes symptoms such as lightheadedness, dizziness, and tachycardia, especially when standing, as well as shortness of breath, brain fog, fatigue, digestive issues, and heat intolerance.“I’d been seeing POTS patients for 30 years, and suddenly we were inundated with them,” said Blair Grubb, MD, an autonomic disorder specialist and director of the Cardiac Electrophysiology Program at the University of Toledo Medical Center in Toledo, Ohio.Prompted by the influx, Grubb investigated the trend across more than 65.1 million patient records worldwide. His study found a 130% increase in the rates of POTS — jumping from 430 cases per month in the 2 years prior to March 2020 to 990 per month in the 4 years after.Now, a condition that was largely overlooked for decades — and only received a diagnostic code in late 2022 — is drawing more scientific attention than ever before. As emerging evidence links POTS to autoimmunity, treatments are shifting from symptom control toward drugs that target the root cause.Does COVID Cause POTS?Most experts agree COVID triggered the rise in diagnoses, but some say greater awareness could also be a factor. “The exact magnitude of the increase attributable specifically to COVID remains uncertain,” said Stavros Stavrakis, MD, PhD, vice chief of the Cardiovascular Diseases Section at the University of Oklahoma Health Campus in Oklahoma City.Pre-pandemic, POTS often went undiagnosed or misdiagnosed, due in part to biases and to a lack of understanding of the condition. “Unfortunately, to be honest, many patients are dismissed because they’re women,” said Grubb.POTS is a heterogenous syndrome, meaning it can be triggered in different ways. Viruses are the most common trigger, followed by pregnancy and then traumas such as car accidents or surgery. An estimated 40% of people with the condition report having had a virus before their symptoms started, with studies showing that infections, such as influenza and Epstein-Barr virus infection, often precede its onset.“Now the bulk of the patients we see in clinic are post-COVID,” said Grubb. Most are also young women, though the reason is not clear. “Potential explanations include sex hormones, differences in vascular physiology and blood volume regulation, and sex-related differences in immune responses and susceptibility to autoimmunity,” said Stavrakis.The Overlap With Long COVIDHannah Harding was initially diagnosed with both POTS and long COVID. “They said that I developed POTS as a part of long COVID, that essentially that was how it was manifesting for me,” said Harding.But evidence suggests that in many cases, the two diagnoses describe the exact same symptoms. Long COVID, also known as postacute COVID-19 syndrome, is an umbrella term for any symptoms that continue for more than 2 or 3 months. “For most long-COVID patients, especially the ones who are disabled with multiple symptoms, their clinical features are very similar, if not identical, to those of POTS,” said Tae Chung, MD, head of a new multidisciplinary POTS and autonomic disorders program at Northwestern University.In one small study, 62.5% of participants with long COVID met the formal diagnostic criteria for POTS and another 20.8% reported orthostatic symptoms but fell short of the full criteria.Grubb’s team has studied the immune profiles of patients who developed POTS before the pandemic vs those with long COVID-associated POTS. “The immunology is virtually identical,” said Grubb. “So I believe what happened is the same syndrome is provoked by a different virus.” In other words, much of what is labeled “long COVID” may actually be the same postviral dysautonomia clinicians have seen for decades, just sparked by a new virus, said Grubb.Research Points to an Autoimmune ComponentHistorically, POTS research has been limited. “One positive consequence of the pandemic is that dysautonomia and POTS have received a level of scientific attention and funding that they never had before,” said Stavrakis.One area of investigation has focused on POTS as an autoimmune disorder driven by “molecular mimicry,” where the immune system mistakes part of the autonomic nervous system for a virus. “It just keeps attacking, inflaming the nerves, which destroys the autonomic nervous system,” said Chung.Grubb’s team published two studies identifying autoimmune factors in people with POTS. In one study of 55 patients with POTS who reported having a virus prior to their symptoms, 89% showed elevated levels of antibodies against alpha-1 adrenergic receptors — the components of the autonomic nervous system responsible for heart contractions and constricting blood vessels.Normally, when we stand, vasoconstriction pushes blood to the heart and brain. This system is weakened in POTS, so blood takes longer to circulate, causing symptoms such as loss of vision, increased heart rate, fatigue, and brain fog.How Treatment Is EvolvingEven though studies on autoimmune factors in POTS still need to be validated, some researchers are moving toward treating POTS as an autoimmune disease.Traditional POTS treatments focus on symptom management — improving vasoconstriction and slowing heart rate with medications, compression garments, and increased salt and fluid intake. Harding takes a beta-blocker to lower her heart rate and has been told to wear compression socks, drink lots of fluids, and take salt to help with blood volume and circulation. But researchers and clinicians are now looking at immune-modifying drugs that could potentially target the root of the problem.“There are so many drugs out there in the market that manipulate your immune system,” said Chung. “If you can actually manipulate the immune system so that the immune system stops inflaming the nervous system, that treats it at a more fundamental level.”Specialists like Chung have been prescribing these drugs off label to certain patients. “Based on that experience, a lot of people speculate that they work pretty well,” he said. But randomized controlled studies are needed to support their widespread use.“We are beginning studies to look at the effects of using the same medications that are employed to treat rheumatologic disorders,” said Grubb. “Why reinvent the wheel? Let’s try to do what they do.”After a long history of being dismissed, patients with POTS may finally see the science catch up.Chung reported receiving consulting fees from argenx and Regeneron Pharmaceuticals. Grubb and Stavrakis reported no relevant disclosures.