As long COVID cases grow, clues emerge about who is most at risk

Eliana Uku wasn’t too worried when she got sick from COVID-19 in March 2020. She was 26 and healthy, she exercised most days, and at first her symptoms were mild. Even with a low fever, cough, fatigue, and mild headache, she kept working in her job as a corporate strategist in New York City. Three weeks after her first symptoms appeared she felt well enough to resume running.

But her cough persisted, and after a month or so, new symptoms appeared, such as memory lapses and sensitivity to sound. Everything was painfully loud, including the sound of her boyfriend washing dishes, leading the couple to switch to paper plates. She would forget words, and her mind would go blank at work meetings. By May she had insomnia, restless legs, and severe nausea. Her heart rate would skyrocket into the 160s after standing for a few minutes, even though she used to be a marathon-runner with a resting heart rate in the high 40s.

Scared and confused, Uku went to the emergency room in May 2020, where a doctor told her that some patients were reporting lingering or even new COVID-19 symptoms—a condition now called long COVID. Now, nearly two years after she first got sick with SARS-CoV-2, Uku still can’t work, and she has had to defer admission to Stanford Business School.

With scientific studies ongoing and a definition in flux, long COVID continues to confuse and frustrate patients and healthcare providers. But estimates of the number of people who suffer from long COVID range from 10 percent to more than 50 percent of all confirmed cases, making it imperative for researchers to understand its causes and effects.

In one important step forward, scientists are now sleuthing out biological risk factors that make some people more susceptible to this condition. In a recent paper, researchers completed the most comprehensive analysis to date of predictors of long COVID, discovering a set of specific conditions that were associated with lingering symptoms.

Figuring out how these factors influence an individual’s COVID-19 trajectory could alert people—either before they get sick or early on in the infection—that they are vulnerable to developing long COVID, says Jim Heath, president of the Institute for Systems Biology, a research nonprofit in Seattle and one of dozens of co-authors on the new paper.

The new study, while thorough, is not the only attempt to identify biological vulnerabilities of long COVID, says Anna Ssentongo, an infectious disease epidemiologist at Penn State College of Medicine in Hershey, Pennsylvania, who was not on the study team. But it’s not the only attempt to identify biological vulnerabilities, she notes. Other studies have zeroed in on genetic factors and even changes in the microbiome as possible risk factors for long COVID.

Eventually, research into these risk factors could lead to personalized treatments for long COVID, says Avindra Nath, the clinical director of the National Institute of Neurological Disorders and Stroke, part of the U.S. National Institutes of Health. It could also reduce the rates of long COVID, he adds, and help legitimize the complaints of people who developed an illness that doesn’t have an obvious test or even a clear definition.

Huge spectrum of symptoms 

Uku encountered much skepticism when she started seeking medical care for her post-COVID-19 problems. Friends and family members doubted her symptoms were real. Doctors prescribed antidepressants and told her boyfriend her illness was probably psychosomatic.

“Patients who have long COVID go to the doctor, and they say they’ve got brain fog, or they can’t sleep or they’re tired all the time, and the doctor just tells them to get some rest or something. And people find that incredibly frustrating. They know something’s wrong with them,” says Heath. “As soon as you can begin to define a condition like that, that’s the first step toward treating it.”

But not everyone was surprised that Uku and people like her were showing up at hospitals and clinics.

Before the pandemic began, Ssentongo was a graduate student looking at long-term illnesses that follow various viral, bacterial, and parasitical infections. Researchers have seen that dementia that can follow HIV infections, she says, and lifelong epilepsy can develop after a severe case of malaria.

When Ssentengo heard about long COVID—known medically as post-acute sequelae of COVID-19, or PASC—she shifted gears and began exploring how common it was. In a review of 57 studies that included more than 250,000 people, she and colleagues reported in October 2021 that 54 percent of people who survived COVID-19 had at least one lingering symptom six months after either diagnosis or discharge from the hospital. In the mostly unvaccinated population included in the review, nearly 80 percent of people had been hospitalized, but rates of long COVID were the same after both mild and severe cases.

Those numbers are still a work in progress. Other studies have found higher rates of long COVID in people with more serious disease. Among people with mild infections who were not hospitalized or in the ICU, Nath says, long COVID rates are closer to 10 percent.

What makes this condition difficult to study and quantify is that long COVID has become a catch-all term for a wide diversity of experiences. In the research Ssentengo reviewed, symptoms ranged from mild to life-threatening. The list of possible issues included memory problems, trouble concentrating, difficulty breathing, joint pain, skin rashes, sleep problems, and symptoms that worsen with exercise. Some problems seem the direct result of viral infection, Ssentengo’s team wrote in the paper, while others may originate from post-traumatic stress and other mental health consequences of the original COVID-19 illness.

That huge spectrum of long COVID symptoms suggests that many processes in the body can trigger the condition, Ssentengo says, and that risk factors for each route will also differ. “There is no one clear set of symptoms, and there are likely different biological causes of each post-COVID condition we see,” she says.

Finding the risk factors

To understand how COVID-19 might cause long-term symptoms, Heath and his colleagues tapped into data from a cohort of people they had started studying at the beginning of the pandemic. Using medical records, surveys, blood samples, and nasal swabs, they mined the data for all sorts of biological and immunological patterns.

The investigation revealed that lingering symptoms were common, a finding that Heath and his team reported in the journal Cell in January. Three months after symptoms began, more than half of participants reported fatigue, a quarter were still coughing, and 18 percent still had trouble with their sense of taste or smell, among other issues. About 35 percent of patients in the study reported between three and 10 symptoms.

Of those with ongoing symptoms, virtually all had at least one of four distinct risk factors: type 2 diabetes; measurable levels of SARS-CoV-2 RNA in the blood during the initial COVID-19 infection; circulating Epstein-Barr virus early in the infection; and a high level of autoantibodies.

Autoantibodies, proteins made by the immune system, can start to attack the body rather than just viral invaders. Having elevated levels of these proteins before even getting an infection was the most common predictor, showing up in two-thirds of people with lingering COVID symptoms, Heath says. A resurgence of Epstein-Barr in people who were previously infected with the virus, which can cause infectious mononucleosis, appeared in one-third of their long COVID cohort. Diabetes and SARS-CoV-2 also showed up in one-third of the long-Covid group. Some patients had multiple factors.

Each risk factor was linked to specific long COVID symptoms. Those with autoantibodies, for example, tended to experience fatigue and respiratory symptoms. Type 2 diabetes was associated with the common symptoms of respiratory viruses, like fatigue. And reactivation of the Epstein-Barr virus was associated with neurological symptoms, such as brain fog, difficulty sleeping, and memory loss.

Those findings corroborated previous results, says Michael VanElzakker, a neuroscientist at Harvard Medical School and Massachusetts General Hospital. For instance, research has connected resurgence of Epstein-Barr with diseases such as multiple sclerosis and chronic fatigue syndrome, also known as ME/CFS.

“I think that the surprising thing is how much of the long COVID these past factors account for,” Heath says, “and the fact that you can see them all at diagnosis.”

The ecosystems inside us

In a review of research on SARS-CoV-2 and other RNA viruses published in October 2021, VanElzakker and his colleague Amy Proal, a microbiologist at PolyBio Research Foundation, a research nonprofit in Kenmore, Washington, proposed a number of other possible routes to long-term symptoms. Among them: The virus might injure organs, persist in tissues, or disrupt the microbiome in ways that could cause inflammation and trigger neurological symptoms. The virus might derail the immune system, spur blood-clots, or disturb nerve signaling in the brain stem and in the vagus nerve, which could lead to symptoms resembling chronic fatigue syndrome.

Or, much like the reactivation of Epstein-Barr, microorganisms that normally inhabit us without causing trouble may start sparking problems when a SARS-CoV-2 infection stresses the immune system.

One pathogen of concern is the parasite Toxoplasma gondii, which is found in cat feces and undercooked meat and lives in an estimated 11 percent of people past infancy in the U.S. It has been linked with cancers, epilepsy, Alzheimer’s disease, and schizophrenia. Studies have suggested that immunosuppressant medications that treat diseases like rheumatoid arthritis and Crohn’s disease—and now severe cases of COVID-19—might reactivate T. gondii into a pathogenic state. Depending on where the parasite ends up, scientists speculate it could cause eye problems, heart problems, or neuropsychiatric issues, among other issues.

That line of research spotlights the vast ecosystems of bacteria, viruses, and other microorganisms that occupy us and have the potential to affect our immune function and health, says VanElzakker.

“We have this ongoing Serengeti inside us,” he says. “When a pathogen comes in and disrupts the immune system, a lot of the stuff that’s in us already can sort of gurgle up and change its behavior, because it’s got the opportunity.”

Researchers are also trawling for genetic variants that raise the risk of severe or long COVID-19. In January, scientists linked two genes to the loss of taste or smell after an infection, which is a symptom that can linger.

Heping Zhang, a data scientist at Yale University, co-authored a study identifying eight genetic variants that confer a higher risk of mortality from COVID-19. Understanding how a gene variant influences the potential for an immune system overreaction, he says, could lead to medications that block that immune response from turning deadly.

Ongoing research is likely to turn up more pre-existing conditions as risk factors for long COVID, Heath says, but it will take larger studies to find them. Another limitation is that most current studies don’t distinguish between symptoms that linger for just a couple months and then go away from those that last longer. People with organ damage after spending time in the ICU are lumped together with people who developed fatigue, dizziness, or trouble concentrating a few weeks after a mild infection. They are not the same, Nath says.

It might also be worth casting a wider net to include environmental factors such as air pollution that might harm the immune system, VanElzakker adds. “That could be something that is a vulnerability factor that we haven’t really thought about and isn’t really being measured.”

Hope and caution for long COVID

Eventually, a biological understanding of long COVID could produce treatments that anyone could take to prevent lingering symptoms. “You get sick, you’re treated aggressively, you’re done,” Nath says. “You don’t even need to know whether you are at risk or not.”

For people with reactivation of viruses like Epstein-Barr, for example, taking antiviral medications very early in an infection might help stave off lingering effects, Heath says. If autoantibodies are an issue, people might benefit from treatments for lupus, which also involves autoantibodies that interfere with the immune system. Identifying genetic links, Zhang adds, could illuminate mechanisms that would suggest other treatment strategies.

There is still a long way to go. Even the strongest predictors identified to date raise questions. Epstein-Barr infection is extremely common, for example; some 90 percent of people harbor the virus in their bodies, making it unclear why reactivation happens only in some cases. Then there are people with multiple risk factors who escape an infection unscathed, VanElzakker adds, while healthier people with fewer risks remain sick for months.

Given the vast and complex number of ways that long COVID can play out, there is unlikely to ever be a simple test or treatment that will work for everyone, VanElzakker says. Instead, his work with chronic fatigue syndrome suggests that multiple hits might be more important than any one risk factor.

“If I had diabetes and a history of clotting problems, and I had bad mononucleosis when I was younger, there’d be a list of things that would cause me to be think long COVID might be a little bit more of a risk for me and I better be extra careful when I go out,” he says. “It’s unlikely that it’s going to be a one-to-one where we just know, Oh, you better not get COVID because you’ll definitely end up with long COVID.”

While researchers continue to probe the underlying mechanisms, one step people can take now to protect themselves is to get vaccinated, Ssentengo says.

In a study of healthcare workers in Israel, 19 percent of 39 people with breakthrough cases reported symptoms that persist beyond six weeks—a lower rate than in studies of unvaccinated people who developed long COVID.

“That study was definitely hopeful that the vaccine potentially could reduce your risk of long COVID,” says Ssentengo, who in the midst of larger studies to determine whether vaccines can avert long-term symptoms. It’s since been backed up by additional research, including an analysis of medical records from more than 240,000 people infected with COVID-19 that also showed far better outcomes for vaccinated people.

For people like Uku, who got sick before vaccines were available, efforts to understand long COVID offer hope for relief along with a sense of validation. She has been thinking back to her freshman year of college in 2011, when she had a serious case of mononucleosis. She wonders if that virus permanently altered her biology and set the stage up for what she’s experiencing now. Still unable to work and eager to start her graduate program, she’s hoping that more insights will come soon.

If she had known that she was vulnerable to long-term consequences of COVID-19, she says, she would’ve made different choices. “I was going into the office and going out up until the day that the lockdown started in New York, and so was my partner,” she says. “Had I known that I was high risk, I would have started isolating the day that the very first case was recorded in New York.”