When 32-year-old artist Hannah Davis fell sick in late March this year, her symptoms were so severe that even watching movies in bed in her Brooklyn apartment was impossible, she says. She began having difficulties reading text messages, and she soon lost the ability to follow a movie plot. 

While some flu-like symptoms, such as exhaustion and a cough, improved over time, her memory loss and other cognitive difficulties have only grown worse, she says, and she also experiences sporadic bursts of blurred vision, a racing heart, difficulties breathing, insomnia, and various aches and pains. “It sounds really insane,” she tells The Scientist. “I’ve been sick for three months, which just sounds so ridiculous to so many doctors.”

While the first physicians she saw didn’t take her symptoms seriously, Davis says, she found support in an online group for COVID-19 survivors battling long-term effects. In an informal survey of 640 of the groups’ members conducted by Davis and others, many report prolonged symptoms, from chest pain and gastrointestinal issues to cognitive problems and debilitating fatigue. Only around 23 percent of respondents had tested positive for SARS-CoV-2, the virus that causes COVID-19, however. Some, like Davis, were denied tests early on because the tests were reserved for the most critically ill (often hospitalized cases only), but based on the bizarre nature of their symptoms that coincided with the wave of coronavirus infections in the US, many members of the online group are certain they have been infected. (Davis later tested negative around a month after symptom onset, when viral loads would normally have faded below detectable levels, but her doctors concluded she had had COVID-19 based on her symptoms.) 

Despite uncertainties around whether some cases are in fact SARS-CoV-2 infections, “long-haulers” such as those in the online group point to the possibility that COVID-19 is not just a transient respiratory disease, but could manifest as neurological and physical symptoms that persist even months after people fall ill. Although many of them may yet recover in the coming months, some scientists are becoming increasingly worried that some may end up with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a debilitating and poorly understood condition associated with some viral infections. In a press conference last week, for instance, National Institute of Allergy and Infectious Diseases Director Anthony Fauci noted that some of the long-haulers’ symptoms resemble those of ME/CFS. Studies are now underway to track whether some long-haulers develop the disease, and if so, to investigate its underlying mechanisms and possible avenues for treatment quickly. 

“This is a massive infection of millions and millions of people. I think one has to be really concerned about the long-term consequences,” notes Avindra Nath, a neurovirologist at the National Institute of Neurological Disorders and Stroke. “A lot of emphasis early on has been on providing treatments and vaccines and antibodies and all that kind of stuff, but the long-term consequences have not received the attention that they deserve.” 

Viral infections and ME/CFS 

A feeling of fatigue and exhaustion isn’t unusual in the aftermath of viral infections, but it usually passes. Accumulating evidence, however, suggests that in some patients viruses could be involved in triggering ME/CFS, a distinct clinical syndrome characterized by lasting fatigue that worsens after exercise or mental exertion—a hallmark physicians call post-exertional malaise. A light walk or completing a questionnaire can leave those with ME/CFS bedridden for days or even weeks. 

“You don’t see that in any other condition,” says Alain Moreau of the University of Montreal who directs a research network for ME/CFS. “We have a large group of patients that are housebound. Even taking a shower could take hours, or they sometimes skip [it] because they cannot do it.” An inability to concentrate, or “brain fog,” is also common in the disease, adds Columbia University immunologist Mady Hornig.

The disease—formerly known simply as chronic fatigue syndrome, or CFS—has long been stigmatized to the point of being ignored by many physicians and researchers, in large part due to its mysterious etiology. Doctors would rule out a number of diagnoses, such as viral infections or neurological diseases, and conclude that there was nothing wrong with such patients, sometimes advising them to simply get more exercise, which would make their condition worse, notes Frances Williams, a genomic epidemiologist at King’s College London. An incident in which a high-profile study purported to identify definitive causes, which later turned out to be false, may also have discouraged scientists from studying ME/CFS, Nath adds. And while some drugs have been trialed in ME/CFS patients over the years, the results so far have been inconclusive, Moreau says, leaving few treatment options for the disease. 

In part because of this long-term neglect of the disease, many patients prefer the term myalgic encephalomyelitis over chronic fatigue syndrome. ME implies a pathological process: an inflammation of the brain and spinal cord. However, Williams and Nath are quick to note that there is so far little evidence for encephalomyelitis in the condition, save for a small Japanese study that found elevated levels of inflammatory markers in the brains of ME/CFS patients and small changes in cytokines in their spinal fluid. Much of the research community, including the US Center for Disease Control and Prevention, have settled on calling the disease ME/CFS. 

Although it’s still a mystery what causes the disease, according to one survey, nearly 75 percent of ME/CFS patients have described viral infections prior to the onset of their symptoms. Other studies have linked particular pathogens, including West Nile, Ebola, and Epstein-Barr viruses, with the development of ME/CFS-like symptoms in substantial numbers of infected people. This association was also observed with SARS-CoV-2’s close relative, SARS-CoV, which caused the SARS epidemic of 2003. One study conducted a year after the SARS outbreak in Toronto found that fatigue was common among survivors, and 17 percent of them still hadn’t returned to work due to long-term health issues. Even three years after Toronto’s SARS outbreak, a study found widespread fatigue and achiness among those who had been infected. 

Such findings leave Moreau with little doubt that SARS-CoV-2 could also leave some people with long-term disability, he says. “With this very severe COVID-19 disease, where we’re now dealing with millions of people suffering from it worldwide, the question is not if [some] will develop ME/CFS—it’s how many.” 

Hornig notes that some of the long-hauler symptoms described in Davis’s report overlap with those common in ME/CFS, although only the passage of time will tell whether some long-haulers will meet the clinical definition of the disease. The rule of thumb is six months, Nath says, citing one of his own ME/CFS studies suggesting that patients rarely recover if their symptoms persist longer than half a year. He and others are now beginning to investigate not just whether, but how SARS-CoV-2 might lead to ME/CFS. 

Mysterious mechanisms 

Although researchers have looked extensively in the blood of ME/CFS patients for evidence of elevated levels of actively replicating viruses, they’ve never found any, Nath says. Some patients, however, exhibit abnormally high levels of certain inflammation-driving molecules, such as interferon gamma or other cytokines, a possible sign of an overactive immune system. “Those are [often] the same cytokines, the same inflammatory markers, that we see are raised in patients with COVID who have the cytokine storm when they’re very sick,” Hornig says. “It may well be that we’re seeing clues about how the immune system is reacting to COVID that actually leads to long-term problems.” 

Normally, the body reins in the immune response after an infection is tamped down, but perhaps SARS-CoV-2 infections could cause the immune system to get stuck in that overactive state in some people, pouring a persistent shower of cytokines into the blood, notes Yale University immunologist Akiko Iwasaki. It’s theoretically possible that the virus could seek long-term refuge in an organ such as the brain that isn’t easily accessible to the immune system, Iwasaki says. This could cause a consistent trickle of virus particles to escape into the blood, where they aggravate an unceasing immune response, she adds, although with a few exceptions, this has never been shown for RNA viruses such as SARS-CoV-2, Nath says. 

Alternatively, the virus itself may be completely eradicated from the body, but leave behind snippets of viral RNA in a reservoir organ. The RNA itself, or the translated protein—which the human body’s own machinery would readily manufacture from the viral RNA—could set off immune reactions once they’re found by the body’s B cells and T cells, Iwasaki and Nath suggest. Possibly in line with this theory, there are some reports of persisting fragments of viral RNA in the throats of people who recovered from COVID-19 months before.  

But the mechanism that Nath considers most plausible is that the immune chaos unleashed by SARS-CoV-2 in some patients somehow triggers autoimmune reactions. On occasion, during the process of instructing T cells which proteins to attack, a macrophage presents one of the body’s own proteins to a T cell. Such rogue T cells are usually eliminated by the immune system, but with the body’s inflammatory signals going haywire during a viral infection, some might escape that culling process, Iwasaki says. A similar mechanism has been proposed for how viral infections could lead to the myelin-attacking autoimmune reactions observed in multiple sclerosis. Interestingly, Italian doctors recently observed autoimmune-like symptoms in severely affected COVID-19 patients that mimic a condition known as Guillain-Barré syndrome. Guillain-Barré has also been linked with infections of certain herpesviruses and Zika virus. 

There are other ways SARS-CoV-2 could lead to autoimmunity, Hornig notes. Once viral RNA or proteins slip inside immune cells—either through infection or other uptake mechanisms—they could disrupt mitochondrial function, altering the cells’ metabolism and function and making them more likely to trigger autoimmune reactions. Perhaps that could help explain why some researchers have found antibodies in ME/CFS patients against receptors of the autonomic nervous system, which controls functions such as blood pressure, heart rate, and breathing, she adds. 

It’s still not clear how immune overactivation could lead to some ME/CFS symptoms, however. It’s possible that chronic immune activation simply drains the body of energy, in a similar way as the growth of tumor cells causes fatigue in cancer patients, Nath suggests. Or maybe the process starts with viral infection in the brain, and that then disrupts the organ’s communication with the immune system, Nath says. “It’s possible that maybe there is some low-grade encephalitis, and [inflammation] in the brain, and that is somehow driving the abnormalities in the immune system and causing this fatigue-like syndrome,” he says. 

There could be other mechanisms at play that don’t necessarily involve autoimmunity, Moreau notes. In an effort to find a biomarker for ME/CFS to help improve clinicians’ diagnoses, he and his colleagues have found in yet-unpublished work that there are unique patterns of microRNA sequences detectable in patients’ blood compared to healthy controls, suggesting that the disease is associated with widespread changes in gene expression. Perhaps viral infections can trigger epigenetic changes in gene expression and downstream metabolic alterations which then cause ME/CFS symptoms, he suggests. 

Hornig says it’s important to keep an open mind to different mechanisms that may be taking place in long-hauler patients as researchers begin to study the phenomenon. 

Tracking long-haulers

If COVID-19 can lead to an autoimmune disease, that process should be evident in patients’ blood in the form of T cells or other immune machinery directed against human proteins, Iwasaki says. She and her colleagues have started collecting blood samples from hundreds of hospitalized patients who have tested positive for SARS-CoV-2 to track their disease and compare the immune profiles of those who recover swiftly with those who don’t. “That would be our first look at whether anything strange is going on,” she says. 

Williams and Hornig are both making use of apps they and others have developed to identify and track the progression of long-haulers. Williams’s app, which encourages people to log SARS-CoV-2 infections and submit regular reports on their symptoms, was released just before the March peak of infections in the UK and has been downloaded by 3 million people so far. Of them, around 3,000 are twins who are part of a long-term study of how genetic factors influence health, and have already provided blood as well as genetic samples before the pandemic. Williams and her colleagues will use the data to try to tease out genetic and immunological factors that help determine who suffers from long-term disease. “That’s going to be essential, I think, for working out what’s going on. Because once you find genetic abnormalities, then [skeptics who still dismiss ME/CFS as a psychiatric disease] will have to accept it,” she says. 

Nath and Moreau, who are both also launching long-term studies of COVID-19 patients’ recovery, see the pandemic as a golden opportunity to finally elucidate what causes ME/CFS, and to find treatment avenues quickly. This will not only benefit COVID-19 survivors, they say, but also the millions of other people worldwide who already have ME/CFS, and whose disease onset is so far in the past that it’s impossible to know what triggered it. 

“I think people—agencies, Congress, everybody—should be really focused” on the possibility that some COVID-19 patients will develop ME/CFS, Nath says. “They really need to appropriate resources to quickly get into this field, get lots of people interested in studying these patients, and try to get the bottom of it. . . . If you don’t do it, it’ll be a missed opportunity.”