Other Viruses Offer Hints Toward the Mystery of Long COVID


August 18, 2022 – Researchers are chasing a slew of potential culprits in the race to find the causes of long COVID. There are a few things they agree on: there will be a number of different causes, and symptoms will vary greatly from case to case.

The two leading theories: The persistence of the coronavirus that causes COVID-19 and an overactive immune response.

There is evidence that the SARS-CoV-2 virus – or at least parts of it – can hide and linger in the body, and it’s possible that this is feeding a sustained, overblown immune response.


Other viruses are known to do this. The Epstein-Barr virus is believed to be the cause of most cases of multiple sclerosis. Chronic fatigue syndrome, long a medical mystery, has also been linked to viral infections.

With a ramped-up immune system meeting a lingering virus, the causes of a long COVID promise to be as numerous as the range of symptoms it produces — according to a recent UK study 62.

Long COVID is a syndrome — a collection of symptoms that can be triggered by different things in different people — says Michael VanElzakker, PhD, of the Department of Neurotherapeutics at Massachusetts General Brigham Hospital in Boston.


“So it doesn’t have to be just one cause, one symptom, one diagnosis, one treatment,” he says. “It’s a convergence of mechanisms that can trigger subjective symptoms in different ways in different people.”

VanElzakker partnered with microbiologist Amy Proal, PhD, to establish the PolyBio Research Foundation in Washington state. It focuses on complex chronic inflammatory diseases such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). You’ve also been dealing with COVID for a long time.

You write in Frontiers in Microbiology in June that long COVID is often described as unusual or mysterious, but it shouldn’t be. For example, it can take months or years for a person to eliminate the Ebola virus. Other syndromes that can be caused by viruses, such as ME/CFS, have been linked to long-term health effects and produce symptoms consistent with long-term COVID.


VanElzakker believes persistent viruses play a key role, but he says skeptics argue tests that find bits of genetic material known as RNA only find harmless remnants. Researchers need to use multiple methods to show that actually leftover viruses may be a cause, he says.

“Which is fair,” he says. “Bold claims require a lot of evidence.”

While a patient may test negative for COVID, these pieces of virus may be lurking in other organs or systems. At the same time, they can also cause your immune system to signal a false alarm response. The data suggest that the immune system may overreact to residual viruses.

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Akiko Iwasaki, PhD, of the Department of Immunobiology at Yale School of Medicine, and colleagues found evidence that long COVID patients’ immune systems are reacting to something.

In a preprint study that has not yet been peer-reviewed, they reported that they found evidence that COVID-19 infection carries herpesviruses – Epstein-Barr virus and varicella-zoster virus, which cause chickenpox and shingles – had reactivated. These herpesviruses never leave the body, and Iwasaki’s team found evidence that patients with long-term COVID illness may have immune systems responding to these reactivated viruses.

They also found evidence of exhausted immune cells known as T-cells and found that the most obvious difference in the blood of patients with long COVID compared to people who didn’t have long COVID was levels of the stress hormone cortisol.


Cortisol levels “alone were the most significant predictor of long COVID classification,” they wrote.

attack lung cells

At the University of North Carolina School of Medicine at Chapel Hill, researchers examined the lungs of mice after clearing the virus to find out what drives the disease.

A team including Richard Boucher, MD, director of UNC’s Marsico Lung Institute, examined mice between 15 and 120 days after the virus was gone and found it had infected cells deep in the lungs. These cells have two key roles: lubricating the lungs and exchanging oxygen for carbon dioxide.

“You get a double whammy early on,” he says. “You don’t have enough of these cells, so they don’t produce the lubricant you need. Your lungs can become stiff and breathing becomes very difficult.”

The immune system is then triggered to eliminate the viral infection. In the mice, it stayed activated for up to 4 months, their research found. “That’s probably the bulk of what’s going on in the lungs in people post-COVID, and that’s going to show up as shadows on a CT scan,” says Boucher.

However, he and others suspect that the immune response to COVID-19 can trigger similar processes as in the early stages of pulmonary fibrosis, a progressive scarring of the lungs.

“You have a lot of extra immune cells in the lungs that shouldn’t have been there, and the immune cells started breaking down fibrous tissue or scars because they couldn’t fix things,” says Boucher.

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His team treated the mice with nintedanib, a relatively new drug for idiopathic pulmonary fibrosis, and it appears to be helping, Boucher says. The FDA approved the drug in 2020 to treat chronic fibrosis (scarring), one of the first treatments for the condition.

In previous work, Iwasaki and colleagues, including Columbia University epidemiologist Mady Hornig, MD, also studied unexplained post-infection syndromes.

“Certain acute infections have long been associated with unexplained chronic disability in a minority of patients,” they write in Nature Medicine. “These post-acute infection syndromes represent a significant public health burden, but a lack of understanding of the underlying mechanisms represents a significant blind spot in the field of medicine.”

That could change with long-COVID research, says Hornig. “The pandemic is one of those turning points,” she says.

The sheer number of patients and the ability to monitor them will provide answers about these syndromes, she says. “We have at least some recognition that there is the possibility of a number of disabling traits that can affect a variety of organ systems,” she says.

What remains unknown, says Hornig, is the extent to which specific pathogens cause critical differences in the individual’s ongoing symptoms.

For example, she believes ME/CFS has multiple causes and has researched things that might play a role. While approximately 75% of patients with ME/CFS report a triggering infection, the remainder do not.

Another theory suggests that small blood clots — blood clots are a hallmark of severe COVID-19 infection — could be at the root of some of the symptoms of a long COVID.

Mass General Brigham’s VanElzakker says the research on this theory has yet to be repeated, but he would be surprised if the blood clots weren’t involved.

Currently, health professionals at long-running COVID clinics across the country are treating the symptoms without waiting for a cause to be proven. Research into what exactly triggers the cascade of events offers hope for new treatments. Studies are ongoing worldwide. The Biden administration pledged support for expanded research in April.


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