For at least a century, scientists and physicians have known that large infectious disease outbreaks often leave a small subset of people with a strange constellation of disabling symptoms that linger long after the initial illness runs its course.

The question they haven’t been able to answer is why — and many are now hoping that the covid pandemic will help solve the mystery.

More than 23 million Americans may be living with some form of long covid, as many as 4 million are out of work because of it, and many more have been forced into diminished lives by the illness. Studies have shown that covid survivors have higher risk of heart problems, blood clots, diabetes and dementia. With the National Institutes of Health pouring more than $1 billion into research on covid’s long-term effects, the pandemic presents a grim opportunity for cracking why some infections lead to chronic illness and developing therapies that might help more than just long covid.

“If we can catch people at the start of their covid, and then study the folks who do go on to develop long covid, we’re in a better position to understand the underlying biology because we’ve been studying them since they first got sick,” said Anthony Komaroff, a professor and physician at Harvard Medical School. “That doesn’t guarantee that the lessons learned in long covid will prove applicable to other post-infectious fatigue syndromes following other infectious agents. But my bet is that it will — that this is all part of the bigger picture.”

That broader picture encompasses a wide range of conditions. Decades after the 1918-1919 influenza pandemic, which infected 500 million people worldwide, epidemiologists discovered many survivors were two to three times more likely to develop Parkinson’s disease than people born at other times. And Epstein-Barr virus, which infects billions worldwide, raises the risk of developing multiple sclerosis 32-fold, according to research published earlier this year.

That same virus may be a cause of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating disease affecting as many as 2.5 million Americans that is characterized by profound exhaustion that often worsens with exertion. Since at least the 1980s, small outbreaks of ME/CFS have suggested the illness — which shares some symptoms with long covid — may be set off by an infection.

Before covid, a relatively small community of underfunded researchers had been plugging away at understanding such conditions, which had been dismissed by many in the medical community as psychosomatic, but many questions remain unanswered.

Now, with the recognition, funding and surplus of research participants covid has wrought, scientists are poised to answer key questions, including how often such syndromes follow an infection or whether there are risk factors. Researchers might learn whether lingering symptoms stem from viruses hiding out in hard-to-reach tissues and how viruses can kick some immune systems into chronic overdrive. If that larger picture comes into focus, researchers might develop new treatments that could help more than just long covid patients.

Success is far from guaranteed. Long covid is likely not one thing but many, and there’s danger in assuming that lessons learned from studying the effects of covid will translate to other conditions. But much could be learned, said Bhupesh Prusty, a molecular virologist at the University of Würzburg.

“We have a unique opportunity to take long covid as a model system to understand how a widespread viral infection can cause post-viral illness later on, whether all post-viral illnesses have similar symptoms and why some people develop these illnesses while others recover completely,” he said. “These are such important questions that have been too long neglected.”

Lingering virus, lingering problems

Perhaps the most straightforward explanation for how viruses cause symptoms long after the initial illness has passed is that they never leave.

Some of the most common diseases stem from viral holdovers. Shingles is caused by a reactivation of varicella-zoster decades after the virus initially caused chickenpox. Cold sores sprout when certain herpes virus strains act up. Joint pain after chikungunya infection, or visual problems following Ebola, could stem from viruses camping out in joints and eye tissue, both of which have been detected.

“It’s not a new concept; people believe in post-viral syndromes, they just don’t really think of it as such,” said Jarred Younger, a neuroscientist at the University of Alabama at Birmingham.

For more mysterious conditions like long covid or ME/CFS, the theory goes that “even though the acute illness seems to have gone away, the triggering agent — or pieces of the agent, proteins that the agent has made — somehow remains, hiding in privileged harbors somewhere in the body,” Komaroff said. “Since it hasn’t been eradicated, it remains a constant goad to the immune system.”

That constant goading can stoke the body into a state of chronic inflammation, making someone feel sick long after the virus stops showing up in normal tests, like a nose swab or blood sample.

Finding those lingering viral particles or debris, and showing that they’re responsible for wide-ranging symptoms, has been challenging. “It’s one thing to have a brain infection and see clear deterioration associated with that, but it’s quite another thing to feel tired and just not back to normal and try to identify how a lingering virus could be doing that,” said Diane Griffin, a virologist at Johns Hopkins University.

That’s especially challenging if it’s unclear what virus to even look for, as is the case with ME/CFS.

Researchers studying chronic fatigue syndrome have long suspected a viral cause (or causes), as there have been numerous outbreaks of the disease and many people with the condition trace their symptoms back to an infection. But it’s difficult to answer the question of whether a pathogen is still in the body without knowing what the pathogen is. It’s also hard to look for viruses in tissues that might be most relevant, like the brain. “It’s hard to do this without getting a piece of the brain and looking to see whether the virus is there or not,” said Griffin, “that always has some risk associated with it.”

A virus lingering in the body after acute infection, particularly in the brain or nervous system, “could make you feel quite crummy,” she said. “The data have not been forthcoming to really make that link. But that doesn’t mean it doesn’t exist.”

Enter long covid

Long covid is different because researchers know what they’re looking for and have some clues on where to find it. SARS-CoV-2 genetic material has been found throughout the body, including the gut, heart and brain, according to a recent autopsy study. “To me, persistence is the most logical hypothesis for what’s driving long covid,” Griffin said.

Researchers studying the long-term effects of covid also have another advantage: Many people with long covid know when they were infected, allowing researchers to directly compare them with people who don’t develop these problems to those who do. That hasn’t been possible at scale with other conditions, like ME/CFS or post-viral Parkinson’s, where people may not have thought much about a run-of-the-mill infection.

But proving cause and effect poses its own challenges. “It’s one thing when you can look under a microscope and see cells dying and signs of inflammation around viral antigens during the acute phase of infection,” said Debby van Riel, a virologist at Erasmus University in Rotterdam, Netherlands. Demonstrating that lingering virus is causing long covid will take more than just finding it around the body, she said.

If such reservoirs turn out to be linked to long covid symptoms, dousing the body with antiviral drugs could prove effective. “We’re currently studying how much antiviral use alters the persistence of RNA in monkeys right now,” Griffin said. While the current crop of antivirals aren’t great — and haven’t been studied in the context of long covid — future versions could prove powerful, perhaps for other viruses, too.

“We need an Operation Warp Speed or Moonshot for antivirals,” said Michael VanElzakker, a neuroscientist at Massachusetts General Hospital and Harvard Medical School. If even a fraction of post-infection syndrome symptoms stem from lingering viruses, improving our arsenal of antivirals could drastically reduce suffering, he said. Some ME/CFS patients are helped by experimental antiviral drugs, but more research and development is needed. “If we really made a push on antivirals, it could make a big difference,” said VanElzakker.

Viral hit and runs

But viruses don’t have to linger to cause long-lasting problems.

In most people, an infection stirs the immune system to unleash a blizzard of activity intended to overwhelm the invader. That torrent of activity is part of what makes us feel sick, but eventually it peaks, and the blizzard becomes a few flurries. But in some people, infections seem to disrupt that natural pattern. Certain parts of the immune system get kicked into a state of chronic overactivation. Even when the virus disappears, the immune blizzard never fully stops, or it becomes too easily triggered.

“The theory is that some immune systems that got ratcheted up to deal with a viral infection never quiet down,” said Maureen Hanson, a molecular biologist at Cornell University. “It becomes dysregulated, and it’s making people feel sick because it’s reacting as if there’s a virus present, even when there isn’t.”

That state of overactivation can lead some immune cells to become, quite literally, exhausted. In people with ME/CFS, natural killer T cells — a type of white blood cell that helps initiate an immune response — become much less active. These cells help keep persistent viruses, such as herpes viruses, in check, and when they become exhausted, those lurking viruses — which likely weren’t responsible for the initial dysregulation — spring back into action.

“It looks like this state of exhaustion results in the reactivation of a lot of the persistent viruses in our body, particularly herpes viruses,” said Liisa Selin, an immunologist at the University of Massachusetts Medical School. This reactivation can overwhelm an already overwhelmed immune system, potentially causing a range of symptoms — including neural cell death — and exacerbating dysregulation. Early evidence suggests long covid patients show similar signs of latent virus reactivation.

Scientists still don’t understand why dysregulation or reactivation happens or whether there are risk factors that predispose some immune systems toward getting out of whack. Studying long covid might offer researchers a chance to see how these processes unfold, and look for genes or environmental factors that might be associated with long covid and potentially other conditions.

Overactive immune systems can also stoke chronic inflammation of the brain’s immune cells (called microglia), which could be causing many of the neurological symptoms that can pop up after an infection, said Younger. “Some viruses may be traumatizing or sensitizing microglia,” he said, causing the cells to stay in a hyper-sensitized state. “As a consequence of being on guard all the time, the person is going to feel sick.”

Brain inflammation might also contribute to other conditions associated with post-infection fatigue, like postural orthostatic tachycardia syndrome, or POTS, which interferes with the functioning of involuntary processes like heart rate, breathing and body temperature.

Such hypersensitivity might also be what’s driving increased risk of Parkinson’s after influenza infection, said Richard Smeyne, a neuroscientist at Thomas Jefferson University who studies the long-term effects of influenza. “It might not be the flu itself causing this, but the viral infection is sensitizing the nervous system to other insults, which will happen later,” he said, including other pathogens or environmental toxins. “Any one of them alone wouldn’t lead to the development of the disease, but when you combine them, they synergize upon one another.”

Any uptick in Parkinson’s disease associated with SARS-CoV-2 would take decades to manifest, said Smeyne, but the pandemic could allow researchers to eventually uncover risk factors for this kind of sensitization. “Nature has given us the first part of the experiment, by infecting millions and millions of people with covid,” he said.

Over time, researchers may be able to see whether people with more exposure to agricultural pesticides, or those who got infected multiple times with SARS-CoV-2, had higher risk of developing Parkinson’s or other neurological disorders, he said.

A tragedy — and an opportunity

There are likely many other ways viral infections can cause lingering illness. Viruses hijack human cells to reproduce, and that replication can sometimes physically damage tissues; in the case of long covid, tiny blood clots potentially spawned by the coronavirus spike protein could be wreaking cellular havoc. Some viruses might cause the immune system to recognize friend as foe and start attacking a person’s own healthy tissues, kick-starting an autoimmune disorder, or they could sap the ability of certain cells to produce and use energy, or throw the gut microbiome out of balance.

It’s likely that many of these factors interact with each other to cause post-viral illnesses, and that understanding long covid and other SARS-CoV-2 complications will only fill out part of the picture. Ensuring that the NIH’s billion-dollar investment in long covid research translates to relief in patients suffering from long covid, and potentially to other post-viral illnesses too, will require listening to all these patients, involving them in the research process and building on existing knowledge.

“The lowest-hanging fruit is to ask patients what their priorities are at the beginning of the research,” said Hannah Wei, a co-founder of Patient-Led Research Collaborative, a group of long covid patients who are also researchers. Not only does that help guide research into possible treatments, but it can spark research questions scientists wouldn’t think to ask.

“Post-exertional malaise, one of the core symptoms of ME/CFS, was articulated by the community of patients,” said Komaroff, who was involved in early research on the condition. “No doctor would have ever thought to ask whether you feel bad the day after exerting yourself physically or mentally, but patients brought it to the attention of doctors.” That helped guide research revealing key physiological differences in how ME/CFS patients respond to exercise.

It’s also important to understand that scientists examining long-term consequences of covid aren’t starting from scratch. “Long covid research is still playing catch-up to ME/CFS research,” said Jaime Seltzer, director of scientific and medical outreach at MEAction, an advocacy group. “We are confirming again and again what we found in smaller [research] cohorts that have been triggered by other viral infections,” she said. Pre-covid research into post-viral illnesses suffered from underfunding, smaller sample sizes and outright dismissal of the reality of these conditions, Seltzer said.

That’s all changed with covid. Doctors or researchers who may have been skeptical of these conditions now may have colleagues suffering from long covid, or are themselves. Long covid research is attracting funding earlier researchers could hardly dream of, and studies can much more easily find patients.

“We just can’t let this go to waste,” said Adriane Tillman, an editor at MEAction who lives with ME/CFS. “It’s such a huge tragedy, but it’s also such a huge opportunity.”