A year and a half into the pandemic, doctors are getting better at recognizing long COVID — the collection of persistent health problems that some people develop after a coronavirus infection — but research has yet to pinpoint what could be driving the illness.
"Most likely it's more than just one condition," said Dr. Francis Collins, director of the National Institutes of Health, which is pouring $470 million into a national study on long COVID. "The really troubling aspects of this terrible pandemic might be the lingering of this long-tail effect on people."
Long COVID is a kind of shape-shifting illness that can span dozens of symptoms — a large international study identified more than 200 of them. Some of the most common include headaches, fatigue, brain fog, and shortness of breath. It can happen after severe and mild infections, in both old and young people.
Anywhere from 10% to 30% of people who get infected with the coronavirus will have persistent symptoms lasting at least one month, according to the Centers for Disease Control and Prevention. Many with long COVID continue to deal with symptoms for many months, even more than a year after the initial infection.
Scientists are pursuing many different lines of research about the possible biological mechanisms underlying the condition, hoping this research will ultimately yield meaningful treatments for the millions of people who are afflicted, sometimes with debilitating symptoms.
Here are four major theories researchers are investigating.
1. Maybe the virus never left
One theory some scientists are looking into is viral persistence. The idea is that someone catches the SARS-CoV-2 virus and eventually gets over the initial infection, but it's possible the virus sticks around in some parts of the body, causing the kinds of persistent symptoms seen in long COVID patients.
"That's one of the first questions we need to answer," says Dr. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke. "Is COVID hiding in the body somewhere?"
This wouldn't be unprecedented. Other viruses are known to linger in parts of the body for months or even years, creating a "viral reservoir" in places where the immune system is not as likely to root it out, says Amy Proal, a microbiologist at the PolyBio Research Foundation, who has proposed a variety of theories for what could be causing long COVID.
"Pathogens, in simple terms, tend to hide in tissue and, in fact, they have a lot of mechanisms to do that," she says. "The proteins they create allow them to better burrow into tissue."
For example, scientists have found evidence of the virus that causes Ebola in tissue and body fluids long after the initial infection. Some Ebola survivors suffer from chronic symptoms, and they appear to have waxing and waning immune responses against the virus, as if they were still infected, Proal says. Recent research even suggests an outbreak of Ebola in West Africa originated with someone who was infected years earlier and had harbored the virus.
Some studies suggest the coronavirus remains in parts of the body, including the gut, well after someone has recovered, although this doesn't necessarily mean the person can spread the virus easily.
This theory of viral persistence would also explain why some people with long COVID start to feel better after receiving the COVID vaccines, because the shot would essentially boost their immune response against the lingering virus. A team at Yale School of Medicine is currently studying this possibility. .
2. Once on, the immune system fails to turn off
The long COVID patients that come to see Dr. Nancy Klimas remind her a lot of another group of patients she's used to treating — people with chronic fatigue syndrome, also called ME/CFS.
"That's an illness that more often than not is post viral," says Klimas, an immunologist at NOVA Southeastern University. "There's a virus that just pushes the on button on the immune system and doesn't seem to release it."
ME/CFS isn't fully understood, either, but Klimas says the viruses that trigger it tend to be the most inflammatory — similar to the SARS-CoV-2 virus, which can be so deadly because it creates such an extraordinarily inflammatory reaction. "So it's not too surprising that the coronavirus would be another trigger of a similar illness," she says.
Many patients and researchers hope that all the attention on long COVID will offer new insights about the mechanisms underlying ME/CFS and other post-viral illnesses, because with the coronavirus there are now so many people who can recall the details of the origin of the illness, says Dr. Peter Rowe of Johns Hopkins University School of Medicine.
"Part of our hope is that the increased interest is going to bring in more scientific firepower to help tackle these unanswered questions," he says.
3. The immune system starts attacking itself
It's possible the virus has triggered autoimmunity in some long COVID patients. This is when a person's own immune system gets confused and attacks tissues and organs in the body.
Researchers have found that a coronavirus infection can lead the body to create certain proteins, called "autoantibodies," that can end up being harmful. Autoantibodies are seen in many autoimmune diseases.
"We found that COVID-19 patients had astonishing numbers of autoantibodies that were actually more than what we see in autoimmune conditions like lupus," says Dr. Aaron Ring, an immunologist at Yale School of Medicine.
Ring is part of a research team that's identified some of these autoantibodies in sick COVID-19 patients. "A lot of the autoantibodies were actually directed against the immune system itself," he says, calling it "immune fratricide."
Those autoantibodies were also directed at many other parts of the body, from the brain and central nervous system to blood vessels and platelets. So far, it appears these autoantibodies can hang around in some patients who had COVID-19 for many months, if not longer.
"That could explain the diverse outcomes that we see in terms of long COVID and how it manifests, but this isn't proven yet," Ring says.
4. Other problem viruses wake up
One more idea: It could be that other viruses people had before getting the coronavirus reemerge during the infection and start to cause problems.
These viruses may have been kept in check when the person was healthy, but it's possible that fighting the SARS-CoV-2 virus dysregulates and throws off their immune system. "This provides a very good atmosphere for these other viruses to reactivate and potentially infect new nerves, new tissue or the central nervous system, even in the brain," says Proal.
Under this scenario, viruses other than the coronavirus could be contributing to the chronic symptoms seen in long COVID. In fact, a recent study found that long COVID patients were more likely to have reactivation of the Epstein-Barr virus — what causes mononucleosis — suggesting COVID-19 caused that virus to reactivate.