Scientists haven’t unraveled the cause of long COVID. But evidence is growing that an ongoing viral infection could be driving the symptoms, at least in some patients.

Gary Waters/Fanatic Studio

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Gary Waters/Fanatic Studio

Scientists haven’t unraveled the cause of long COVID. But evidence is growing that an ongoing viral infection could be driving the symptoms, at least in some patients.

Gary Waters/Fanatic Studio

Brent Palmer’s first inkling about long COVID started in the early days of the pandemic, before the term “long COVID” even existed.

Some of his friends had caught the virus while on a ski trip and returned home to Colorado with the mysterious, new illness. It was a frightening time — and an irresistible opportunity for Palmer, who studies the immune response to infectious diseases like HIV.

In particular, he was keen to see how their T cells, part of the immune system’s arsenal for fighting infections, were handling the novel infection. So he started taking samples of their blood. And there was one subject in particular who intrigued him. She was still dealing with heart palpitations, chest pains and trouble breathing more than six weeks after her acute illness.

In the lab, Palmer noticed that she still had a very high percentage of these T cells directed at the virus compared to her husband who’d also fallen ill, but didn’t have lingering symptoms. “They had very different responses,” says Palmer, an associate professor of medicine at the University of Colorado.

Typically, T cells aimed at the virus reach very high levels during the acute infection and over time they drop off, but Palmer noticed that wasn’t the case as he began studying more patients with these persistent symptoms.

“These individuals had frequencies that were 100-fold higher in some cases than the individuals that didn’t have any persistent symptoms,” he says.

In fact, Palmer says it was like their body was still fighting the virus. It led him to questions: “Despite the fact that they test negative in a nasal swab, is the virus still persisting in the lungs? Is it persisting in some other organ?”

Other scientists trying to uncover the roots of long COVID have asked some version of that same question for the last few years now. This theory of “viral persistence” posits that some people never fully eliminate the infection, that viral reservoirs are subsisting in the body and possibly triggering the symptoms of long COVID.

While a direct link isn’t yet proven, this line of research has gained momentum as more evidence has emerged indicating that some people seem to harbor “viral reservoirs” after their initial illness has passed. It’s far from the only explanation under consideration, but some scientists see it as one of the most promising.

“There’s enough evidence to place viral reservoirs as one of the leading drivers of long COVID,” says microbiologist Amy Proal, who’s president of PolyBio Research Foundation, which is spearheading research into viral persistence.

A reservoir… but where?

Much of the research related to viral persistence has come from two sources: evidence of the virus persisting in different parts of the body and signs that the immune system is still revved up in some people months after the acute illness.

For example, Palmer and his team ultimately found that patients with long COVID had higher frequency of T cells specific to the virus than those who didn’t have persistent symptoms — and that was also associated with higher levels of systemic inflammation, worse lung function and longer duration of symptoms like cough and difficulty breathing. Other teams have made similar types of observations about the ongoing immune response in long COVID patients.

Then there are all the corners of the body where scientists have discovered that genetic material or proteins from the virus appear to linger. Patients with persistent symptoms have traces of the virus in their stool many months after being infected, while tissue samples from the gut have also shown evidence of viral persistence. In other reports, biopsies taken from different parts of the body have led to similar conclusions, that parts of the virus can be recovered from some patients many months later.

A painstaking autopsy study, published at the end of last year, has also strengthened the case for viral persistence.

By examining people who died following a case of COVID-19, Dr. Daniel Chertow was able to find evidence of the “virus in over 30 different cell types” and “in tissues throughout the body and all the major organs.”

In one case, there was genetic material from the virus in a person who died more than 200 days after contracting COVID-19. In another, Chertow and his team were able to culture virus from tissue samples taken from the brain of someone who’d died within two weeks of their illness.

“It provides definitive evidence that the virus is capable of spreading all over the body and that it’s capable of persisting in parts all over the body,” says Chertow, who’s an investigator at the NIH Clinical Center and the National Institute of Allergy and Infectious Diseases.

Chertow cautions that only so much can be extrapolated from the study because it wasn’t examining long COVID patients specifically. The subjects also tended to be older and had underlying health problems — a very different population than those with long COVID who were healthy and had a mild case of COVID-19 before developing chronic symptoms.

“Ultimately, the role of viral persistence in causing or contributing to the clinical symptoms and signs that people with long COVID experience is yet to