Long COVID Research Is in Its ‘Most Hopeful’ Phase Yet

A phenomenal amount of research on Long COVID—the name for chronic symptoms following a case of COVID-19—has been published over the past three years. But scientific advances have yet to bring relief to people who are already sick, a group estimated to include about 5% of U.S. adults but hard to precisely quantify due to the difficulty of diagnosing people correctly.

Researchers are optimistic that breakthroughs are coming. The U.S. National Institutes of Health (NIH) has launched multiple clinical trials focused on potential therapies, and several recent studies have pointed to biomarkers that may help doctors accurately diagnose—and, hopefully, treat—people with Long COVID.

“In the short history of studying this disease, this is probably the most hopeful moment we’ve ever had,” says Christoph Thaiss, an assistant professor of microbiology at the University of Pennsylvania’s Perelman School of Medicine who co-authored a recent study on Long COVID in Cell.

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The search for biomarkers

Long COVID is currently a disease mostly defined by its symptoms, which range from brain fog and fatigue to headaches and nervous-system dysfunction. There is no single test that can diagnose it—although recent research points to a variety of potential testing methods, from full-body scans to eye exams.

A September study published in Nature was widely heralded as a step toward finally having a blood test to confirm Long COVID. Researchers analyzed blood samples from almost 300 people, some of whom had Long COVID, some of whom had never had COVID-19, and some of whom had it and fully recovered. Long COVID patients tended to have low levels of the stress hormone cortisol, and their blood also often suggested that virus lingered in their bodies—either remnants of the virus that causes COVID-19, or other viruses that had been dormant in the body after prior infections and become reactivated.

Co-author Akiko Iwasaki, an immunobiologist who directs Yale University School of Medicine's Center for Infection and Immunity, says it's unlikely there will ever be a single biomarker for Long COVID, since the disease can look very different from person to person. But when a machine-learning model was trained to pick up on all of those potential signals together, it was able to distinguish the blood of Long COVID patients from the blood of people without the condition with 96% accuracy.

“That doesn’t mean we’re going to have biomarkers next week,” Iwasaki says, “but I think we are moving forward in the right direction.”

Thaiss’ recent study in Cell found another potential biomarker in the blood of Long COVID patients: low levels of the neurotransmitter serotonin, which is largely produced in the gut and involved in numerous bodily functions. Using stool samples, Thaiss and his colleagues found genetic material from the SARS-CoV-2 virus in the gastrointestinal tracts of a subset of Long COVID patients, mirroring results from other studies. They then hypothesized, and used mice to demonstrate, that this stubborn viral material can trigger an immune response that leads to excess inflammation in the body, in turn hampering the gut’s production of serotonin. Inadequate serotonin seems to contribute to a number of neurological symptoms of Long COVID.

The study is important because it “gets us closer to understanding what’s happening” in the bodies of people with Long COVID, says Hannah Davis, one of the leaders of the Patient-Led Research Collaborative for Long COVID.

Low levels of cortisol or serotonin could be useful "signals" for assessing people with Long COVID, but—at least for now—they cannot serve as stand-alone diagnostics, says Dr. Adupa Rao, medical director of the COVID Recovery Clinic at the University of Southern California’s Keck School of Medicine. For one thing, the studies on potential Long COVID biomarkers have been fairly small and must be replicated in larger groups of patients, Rao says. Beyond that, there are plenty of reasons why someone would have low cortisol or serotonin, including non-COVID viral infections, he says.

Will biomarkers lead to treatments?

Still, Maayan Levy, who co-authored the Cell study and is also an assistant professor of microbiology at UPenn, believes serotonin may be a target for Long COVID treatment. Building on their findings in mice, her group is designing a clinical trial to test whether selective serotonin reuptake inhibitors (SSRIs)—a widely prescribed class of antidepressant, including fluoxetine (Prozac) and escitalopram (Lexapro), used to boost serotonin levels in the brain—are effective against Long COVID. She also plans to test whether supplementing tryptophan, an amino acid that the body uses to make serotonin, may be beneficial.

But Davis is skeptical. SSRIs are already so widely used, she says, that “if SSRIs worked, we would know.” And researchers working on ME/CFS, a condition similar enough to Long COVID that many long-haulers meet its diagnostic criteria, have previously warned that tryptophan supplementation may be dangerous for patients. “It would be good to not reinvent the wheel” by re-testing these ideas, Davis says, noting that there is plenty of research on ME/CFS treatment that could inform researchers working on Long COVID.

In her view, there are other, more promising possible treatments in the research pipeline, including antivirals (which could, in theory, destroy remnants of either reactivated viruses or the SARS-CoV-2 virus lingering in the body); drugs that interact with the immune system; and medications that prevent blood clotting.

Rao says he's not sure any drug currently being studied will become a magic bullet, but he’s encouraged by the field’s progress. “My hope is, in the near future, we’ll be able to identify the cause [of Long COVID] and therefore provide more thorough treatment options, rather than treating just the symptoms,” Rao says.

In Davis' view, testing treatments may achieve both goals: “Understanding what drugs help patients," she says, "will also help us understand what’s actually happening in patient bodies.”