March 7, 2022 11:00 AM EST

Two years into the COVID-19 pandemic, questions about Long COVID still outnumber answers. Why do some people develop long-lasting symptoms—often after a mild case of COVID-19, sometimes even after being vaccinated—while others fully recover from their brushes with the SARS-CoV-2 virus? Why does Long COVID seem to disproportionately appear in women? How can one condition affect numerous bodily systems, causing symptoms ranging from brain fog to joint pain to total exhaustion? Is Long COVID a single diagnosis, or is it better understood as an umbrella term for a spectrum of disease, caused by a range of biologically diverse effects of the virus? Or, could it actually be a new manifestation of post-viral illnesses that have been around for decades?

A flurry of recent studies, some of which have been peer-reviewed and published, and others that are currently going through that process, seek to explain why millions of people suffer from Long COVID. Each one contributes a small piece to the larger research puzzle, helping to build scientific understanding of the disease, little by little.

Even as they do, though, the number of people living with Long COVID grows every day, and there are still few research-backed treatments to offer them. “Patients are pushing for an answer. They’re pushing for the one treatment,” says Christina Martin, a nurse practitioner who helps run Dartmouth-Hitchcock Medical Center’s Post-Acute COVID Syndrome Clinic in New Hampshire. “They’re looking for the Holy Grail, and it’s just not out there.”

Causes of Long COVID

Dozens of studies on Long COVID have been published in recent months, many of which can be broadly sorted into two camps. One group explores what goes wrong in the body to cause Long COVID symptoms, while the other seeks to identify which individuals are at greatest risk for developing the condition.

The most recent, published in Nature on March 7, suggests that SARS-CoV-2, the virus that causes COVID-19, can damage the brain—even among people who experienced mild cases. This, the authors write, could lead to lasting issues including cognitive decline, smell loss, and inflammation of the nervous system.

In a similar vein, research set to be presented at the European Congress of Clinical Microbiology and Infectious Diseases in April suggests that damage to the vagus nerve—which extends from the brain down the torso—is behind many Long COVID symptoms. After studying almost 350 patients with Long COVID, the researchers found that 66% had symptoms indicative of vagus nerve damage, including abnormal heart rate, dizziness, and gastrointestinal problems. Another recent study, published March 1 in the journal Neurology: Neuroimmunology and Neuroinflammation, also points to nerve damage as a likely culprit behind many symptoms.

But for a condition as complex as Long COVID, which is linked to more than 200 different symptoms, there will likely not be a single cause, says Dr. Gemma Lladós, an infectious disease physician at Hospital Germans Trias i Pujol in Spain and one of the researchers behind the vagus nerve study. Nerve damage may explain many cases, but it almost certainly can’t explain them all, she says.

The vascular system is another area that has drawn attention from researchers. A study published in Biochemical Journal in February argues that tiny “microclots” in the blood may cause many Long COVID symptoms by preventing oxygen from reaching the body’s tissues. Similarly, a paper published in the journal Chest in January suggests that one hallmark of Long COVID, intolerance to exercise, may be related to poor oxygen delivery.

Other researchers theorize that remnants of the SARS-CoV-2 virus may linger in the body, potentially causing lasting symptoms. It’s also possible that, for some people, COVID-19 pushes the immune system into a hyperactive state, essentially causing it to attack itself.

That hypothesis dovetails with a paper published in the journal Cell in January, which tried to explain why some people develop Long COVID and others don’t. The researchers found four key risk factors associated with developing Long COVID:

  • a type 2 diabetes diagnosis
  • genetic material from the SARS-CoV-2 virus in the blood
  • evidence of Epstein-Barr virus in the blood
  • the presence of autoantibodies—molecules that attack the body’s own tissues, instead of foreign pathogens like a virus

Co-author James Heath, president of Seattle’s Institute for Systems Biology, says the autoantibody finding was the most important, in part because it showed a possible similarity between Long COVID and the autoimmune disease lupus. While there’s no cure for lupus, “there are treatments out there that can be effective,” Heath says. “So those would be a line of things that are worth looking at” for Long COVID patients.

The finding that SARS-CoV-2 or Epstein-Barr viruses in the blood can predict some cases of Long COVID also suggests that taking antivirals shortly after a COVID-19 diagnosis could help prevent some cases, he says.

The Treatment Gap

At the moment, though, those are just hypotheses. At least until more research is done, knowing about risk factors does little to help people who already have Long COVID, says Martin from Dartmouth-Hitchcock—especially since most people have no idea whether they have something like autoantibodies in their systems.

Patients often ask about studies they’ve read about risk factors and all Martin can tell them is that, “‘it’s not changing how we manage your symptoms,’” she says. “‘What might make you at risk for it, it doesn’t change things. You have it.’”

Even symptom management is, at this point, a sophisticated game of trial and error, says Dr. Jeffrey Parsonnet, an infectious disease physician who also works in Dartmouth-Hitchcock’s clinic. Some of the interventions that seem to work best for patients in his clinic—like occupational therapy and mental health support—have little to do with the basic science described in studies. “One of the biggest things we have to offer is a knowledgeable and sympathetic ear,” Parsonnet says.

Dr. Brad Nieset, who runs the Benefis Health System Post-COVID-19 Recovery Program in Montana, says his approach hinges on meeting each patient’s recovery goals, whether that’s feeling well enough to sing in church or getting back to an outdoor activity. While his team stays up-to-date on the latest research, Nieset says it sometimes feels that “people are grasping at zebras [rather than looking for horses]. It’s not as complex once you break it down” and focus on what could actually help each individual patient. Often, that means applying long-used treatments—like respiratory therapies or neurologic support—to a new disease, he says.

A better understanding of risk factors could be useful, Nieset says, if vulnerable individuals could seek care right after they test positive for COVID-19. But, again, many risk factors identified by studies, such as autoantibodies or viral load in the blood, aren’t something the average individual would know they have.

As such, “there’s no direct implications of that,” as far as developing screening standards or patient treatments, Parsonnet says.

Dr. Onur Boyman, a clinical immunologist at the University of Zurich, disagrees. He co-authored another recent paper on risk factors for Long COVID, published in January in Nature Communications. His team found that older people, those with a history of asthma, and people with low levels of certain immunoglobulins (which are a type of antibody) were at increased risk of developing Long COVID. People who experienced many different symptoms during their acute COVID-19 infections also seemed at higher risk than those who had few symptoms.

While most people don’t know much about their immunoglobulin levels, Boyman says that testing is fairly easy and inexpensive to do. “If you have patients who are of older age and/or have a history of asthma, then you could measure their immunoglobulin levels. If those are also relatively low, then you would know this individual has a particularly high risk of developing Long COVID,” he says.

Armed with that knowledge, he says, “you can make sure that individual is very well vaccinated,” perhaps getting more regular booster shots than the average person, Boyman says. Studies have shown that vaccinated people who get infected are about half as less likely to develop Long COVID, compared to unvaccinated people.

Beyond Long COVID

Even if studies don’t immediately translate to treatments, it’s important to understand how a disease works and who is affected. That’s especially true for a condition as complicated as Long COVID; if studies begin to suggest that there are actually different subtypes of Long COVID, that could lead to more personalized patient care, Boyman says.

Long COVID is also part of a much wider network of chronic diseases. It seems to overlap especially significantly with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—a condition that can follow viral illnesses and leads to debilitating exhaustion—to the point that some Long COVID patients meet the diagnostic criteria for ME/CFS.

Complex chronic conditions such as ME/CFS, chronic Lyme disease, and fibromyalgia have been around since long before COVID-19 existed and affect millions of people in the U.S. alone, but they have not historically received much research funding or attention from the mainstream medical community. “ME has a 40-year history that’s defined by neglect and abandonment,” says patient advocate Rivka Solomon, who has had ME/CFS for 32 years.

While Solomon says she’s thrilled by the amount of attention given to Long COVID and stresses that there is no “us versus them” in the chronic disease world, she wishes other complex illnesses received the same amount of attention and funding—like the $1.15 billion over four years Congress gave the National Institutes of Health in 2020 to support research into the long-term effects of COVID-19.

Part of the imbalance may have to do with the scale and immediacy of the Long COVID problem. Experts estimate there are upward of 15 million Long COVID patients in the U.S. and even more around the world, all of whom have gotten sick over the last two years. There are up to 2.5 million ME/CFS patients living in the U.S., by contrast. But if researchers had invested in ME/CFS and other post-infectious chronic illnesses earlier, Solomon says, they might have better answers for Long COVID patients today.

Heath argues that all the attention on Long COVID could lead to breakthroughs for other conditions. If researchers learn more about how chronic disease works, it could over time lead to improvements for people who live with a variety of different ailments, he says. Research is “not really just about Long COVID. It’s about the triggers that can lead to the development of chronic diseases.” (Solomon says she’d like to see more studies focus specifically on conditions like ME/CFS, rather than assuming Long COVID findings will translate to other diagnoses.)

Science is progressing, but that progress can feel painfully slow for both Long COVID patients and those who got sick from other viruses well before them. It can take years for hypotheses to turn into solutions—years patients will never get back.

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Write to Jamie Ducharme at [email protected].

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