New Research into What Causes Long COVID

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Feb. 7, 2022 -- Jamie Cantrell was the picture of health when she contracted COVID-19. The 44-year-old marketing executive from Lewisville, TX, had been an athlete all her life and was training for a half marathon when a headache like no other prompted her to take a test.

Even after a positive COVID-19 test result, Cantrell was able to quarantine in her basement and continue working as normal.

A few weeks after recovery, Cantrell returned to running, which is when she started to feel numbness in her foot. Guessing it might be the wrong pair of running shoes, she bought new ones and kept going. The numbness kept traveling up her leg until eventually, she had “head-to-toe” neuropathy. Cantrell joined the millions of other people with long-haul COVID, which may impact as many as 40% of COVID-19 survivors.

Until recently, little research existed to allow doctors to determine who might develop long-haul COVID. Cases range from those who had experienced severe acute COVID-19 to those like Cantrell, whose initial illness was extremely mild. Now, however, a collaborative study is shedding some light on what factors may contribute to long-haul COVID, also known by the medical term PASC (post-acute sequelae of COVID-19).

Researchers identified four main risk factors for PASC:

  • The presence of particular autoantibodies
  • A high viral (RNA) load
  • Type 2 diabetes
  • Reactivation of the Epstein-Barr virus, which sits latent in the blood of most people following a childhood infection

Jim Heath, PhD, president of the Institute for Systems Biology in Seattle, was the principal investigator of the study. He says that some of the nearly 300 patients enrolled had just one factor, while others had overlap of two or more.

“We saw overlap with other PASC factors, but we don’t know if that might portend to more serious long COVID,” he says.

Some of the risk factors were more predictable than others.

“When we do a study of this size, you’re going to have quite a few with type 2 disease,” Heath says. “We can’t conclude that diabetes itself puts you at higher risk, or if it’s the many underlying health conditions that go along with it.”

A high viral load was also not entirely surprising, especially when most of the study participants were early COVID-19 patients, predating vaccines.

“High viral markers in blood probably indicate severe disease and that may have a strong effect on a patient’s long-term recovery from the disease,” Heath says. “These viral signatures tell us that vaccines, plus potentially early intervention with anti-virals could, make a difference in PASC.”

A third risk factor -- autoantibodies -- are essentially the opposite of antibodies, which vaccines provide and help fight the virus. Autoantibodies, however, attack your own proteins rather than foreign pathogens, altering your immune response. While everyone has autoantibodies, those with high levels don’t respond to severe diseases as well.

Researchers discovered that the final risk factor, the Epstein-Barr virus (EBV), had a strong tie in to the neurological symptoms typically associated with long-haul COVID.

“My hypothesis here is that most of us have latent EBV in our blood and when you get COVID, the immune system is suddenly paying a lot of attention to this new virus,” Heath says. “It then reactivates EBV.”

This checks out with Cantrell’s case of long-haul COVID.

“I’m working with an integrative doctor now and he tested for several things, EBV among them, which showed up high,” she says. “My early long COVID showed up as small-fiber sensory neuropathy, and it went into remission for several months last summer.”

In October, however, Cantrell developed a sinus infection, and began experiencing nausea, vertigo, and a racing heart rate. Now she has POTS, or postural orthostatic tachycardia syndrome, another illness common to long-haul COVID-19 patients.

“I’ve had to redefine for myself what I can and can’t do,” she says. “But along with my doctor, we’re digging deeper to find the root causes of my illness.”

Where to Go From Here

While the new study was small, it was a big first step in identifying where the medical community might be headed with long-haul COVID treatment in the future.

“For most of the conditions we’ve identified as associated with [long COVID], treatments exist,” Heath says. “It’s striking to think that we may soon be able to identify who might get [long COVID] at the time of infection. We’re learning it’s not just a random luck occurrence, but that some people have higher susceptibility.”

The earlier you can detect COVID, Heath says, the earlier the medical community might be able to begin a type of treatment, potentially warding off eventual long COVID.

“Some of the treatments for these risk factors are very good,” he says, “such as the antivirals, which could significantly diminish the load carried forward.”

Follow-up studies are necessary, but Heath remains optimistic that the mystery of long-haul COVID will be solved. “This was a big step and the willingness of the patients to help us unravel this disease was a really big deal,” he says.

For Cantrell, the study -- along with her new doctor’s approach to helping her -- offer hope for the future.

“For the long-haul community, there’s a wide array of suffering,” she says. “It can feel like slow progress, and that’s tough when you don’t feel well. But we will find an answer; don’t lose hope.”

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