Many Covid-19 patients experience lingering symptoms months after their diagnosis, a condition known as long Covid, but doctors and scientists have not yet determined why. Now, a new study published in Cell has found four factors that might increase a person's risk of developing the condition.

Recovery clinics for Covid-19 long-haulers

4 factors that may increase your risk of developing long Covid

For the study, researchers analyzed the blood and nasal swabs of 209 people between the ages of 18 and 89 who developed Covid-19 during 2020 or early 2021 and were seen at Swedish Medical Center or an affiliated clinic. Patients were studied at the time of diagnosis, acute disease, and two to three months post-symptom onset.

The researchers then surveyed the patients regarding 20 symptoms associated with long Covid and corroborated the reports with electronic health records. Some of the findings were also corroborated in a separate group of 100 patients to validate findings from the primary cohort.

Results were compared to data from a control group of 457 healthy people.

According to Jim Heath, principal investigator of the study and president of the Institute for Systems Biology, 37% of the participants in the study reported at least three long Covid symptoms two or three months post-infection, while 24% reported one to two symptoms, and 39% reported none.

The researchers found four factors that were associated with an increased risk of developing long Covid:

1. The level of coronavirus RNA in a patient's blood early in their infection, which indicates their viral load
2. The presence of certain autoantibodies
3. The reactivation of the Epstein-Barr virus, which infects most people when they're young but typically becomes dormant
4. Having Type 2 diabetes

According to Heath, the most influential factor in developing long Covid appeared to be the presence of autoantibodies—antibodies that mistakenly attack tissues within the body—which showed up in two-thirds of long Covid cases.

Takeaways from the findings

The study "stresses the importance of doing measurements early in the disease course to figure out how to treat patients, even if we don't really know how we're going to use all that information yet," Heath said.

"We did this analysis because we know patients will go to physicians and they'll say that they're tired all the time or whatever, and the physician just tells them to get more sleep," Heath added. "That's not very helpful. So, we wanted to actually have a way to quantify and say that there's actually something wrong with these patients."

According to Steven Deeks, a professor of medicine at the University of California, San Francisco, who was not involved in the study, the research is "the first real solid attempt to come up with some biologic mechanisms for long Covid."

Deeks cautioned that the findings need to be verified by other research, but still, "[t]hey've identified these four major factors. Each is biologically plausible, consistent with theories that other people are pursuing, and importantly, each is actionable. If these pathways get confirmed, we as clinicians can actually design interventions to make people better. That is the take-home message."

Avindra Nath, chief of the section on infections of the nervous system at the National Institute of Neurological Disorders and Stroke, said the study was well designed but noted some weaknesses, including the short follow-up period of just two to three months.

"This might be too short a time frame," he said. "Some might just improve spontaneously with time."

However, Nath noted that the reactivation of the Epstein-Barr virus made sense, because the virus has been awakened by other diseases and its reactivation has been connected to conditions like chronic fatigue syndrome—a condition that some cases of long Covid resemble.

Akiko Iwasaki, an immunologist at Yale University, said the study is "a great resource for the community studying long Covid," but noted that 71% of the patients in the primary group were hospitalized, meaning it's difficult to say whether the four biological factors are as relevant for patients with mild cases of Covid-19.

However, the finding that patients with high viral loads early on typically develop long Covid means doctors could give patients antivirals soon after their diagnosis to help prevent long-term symptoms, experts said.

"The quicker one can eliminate the virus, the less likelihood of developing persistent virus or autoimmunity, which may drive long Covid," Iwasaki said. (Belluck, New York Times, 1/26; Bean, Becker's Hospital Review, 1/25)