Long-COVID Cases Rise as Stigma of Chronic Fatigue Taunts

Carrie Arnold

January 14, 2021

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

When Margot Gage-Witvliet began feeling run down after her family returned from a trip to the Netherlands in late February, she initially chalked up her symptoms to jet lag. Three days later, however, her situation went from concerning to alarming as she struggled to breathe. "It felt like there was an elephant sitting on my chest," she said.

Her husband and daughters also became ill with COVID-19, but Gage-Witvliet was the only one in her family who didn't get better. After an early improvement, a rare coronavirus-induced tonic-clonic seizure in early April sent her spiraling back down. Gage-Witvliet spent the next several weeks in bed with the curtains drawn, unable to tolerate light or sound.

Today, Gage-Witvliet's life looks nothing like it did 6 months ago when she first got sick. As one of COVID-19's so called long haulers, she continues to struggle with crushing fatigue, brain fog, and headaches — symptoms that worsen when she pushes herself to do more. Across the country, as many as one in 10 COVID-19 patients are reporting illnesses that continue for weeks and months after their initial diagnosis. Nearly all report neurologic issues like Gage-Witvliet, as well as shortness of breath and psychiatric concerns.

For Avindra Nath, MD, a neurologist at the National Institutes of Health, the experience of these long-haul COVID-19 patients feels familiar and reminds him of myalgic encephalomyelitis, also known as chronic fatigue syndrome.

Nath has long been interested in the lingering neurologic issues connected to chronic fatigue. An estimated three-quarters of all patients with chronic fatigue syndrome report that their symptoms started after a viral infection, and they suffer unrelenting exhaustion, difficulties regulating pulse and blood pressure, aches and pains, and brain fog. When Nath first read about the novel coronavirus, he began to worry that the virus would trigger symptoms in a subset of those infected. Hearing about the experiences of long-haulers like Gage-Witvliet raised his suspicions even more.

Unlike COVID-19 long haulers, however, many patients with chronic fatigue syndrome go at least a year with these symptoms before receiving a diagnosis, according to a British survey. That means researchers have had few opportunities to study the early stages of the syndrome. "When we see patients with myalgic encephalomyelitis, whatever infection they might have had occurred in the remote past, so there's no way for us to know how they got infected with it, what the infection was, or what the effects of it were in that early phase. We're seeing them 2 years afterward," Nath said.

Nath quickly realized that studying patients like Gage-Witvliet would give physicians and scientists a unique opportunity to understand not only long-term outcomes of COVID-19 infections, but also other postviral syndromes, including chronic fatigue syndrome at their earliest stages. It's why Nath has spent the past several months scrambling to launch two National Institutes of Health (NIH) studies to examine the phenomenon.

Although Nath said that the parallels between COVID-19 long haulers and those with chronic fatigue syndrome are obvious, he cautions against assuming that they are the same phenomenon. Some long haulers might simply be taking a much slower path to recovery, or they might have a condition that looks similar on the surface but differs from chronic fatigue syndrome on a molecular level. But even if Nath fails to see links to chronic fatigue syndrome, with more than 92.5 million documented cases of COVID-19 around the world, the work will be relevant to the substantial number of infected individuals who don't recover quickly.

"With so many people having exposure to the same virus over a similar time period, we really have the opportunity to look at these manifestations and at the very least to understand postviral syndromes," said Mady Hornig, MD, a psychiatrist at Columbia University in New York City.

The origins of chronic fatigue syndrome date back to 1985, when the Centers for Disease Control and Prevention (CDC) received a request from two physicians — Paul Cheney and Daniel Peterson — to investigate a mysterious disease outbreak in Nevada. In November 1984, residents in and around the idyllic vacation spot of Incline Village, a small town tucked into the North Shore of Lake Tahoe, had begun reporting flu-like symptoms that persisted for weeks, even months. The doctors had searched high and low for a cause, but they couldn't figure out what was making their patients sick.

They reported a range of symptoms — including muscle aches and pains, low-grade fevers, sore throats, and headaches — but everyone said that crippling fatigue was the most debilitating issue. This wasn't the kind of fatigue that could be cured by a nap or even a long holiday. No matter how much their patients slept — and some were almost completely bedbound — their fatigue didn't abate. What's more, the fatigue got worse whenever they tried to push themselves to do more. Puzzled, the CDC sent two Epidemic Intelligence Service (EIS) officers to try to get to the bottom of what might be happening.

Muscle Aches and Pains With Crippling Fatigue

After their visit to Incline Village, however, the CDC was just as perplexed as Cheney and Peterson. Many of the people with the condition reported flu-like symptoms right around the time they first got sick, and the physicians' leading hypothesis was that the outbreak and its lasting symptoms were due to chronic Epstein-Barr virus infection. But neither the CDC nor anyone else could identify the infection or any other microbial cause. The two EIS officers duly wrote up a report for the CDC's flagship publication, Morbidity and Mortality Weekly ReportI (MMWR), titled Chronic Fatigue Possibly Related to Epstein-Barr Virus — Nevada.

That investigators focused on the fatigue aspect made sense, says Leonard A. Jason, PhD, professor of psychology at DePaul University and director of the Center for Community Research in Chicago, because it was one of the few symptoms shared by all the individuals studied and it was also the most debilitating. But that focus — and the name "chronic fatigue syndrome" — led to broad public dismissal of the condition's severity, as did an editorial note in MMWR urging physicians to look for "more definable, and possibly treatable, conditions." Subsequent research failed to confirm a specific link to the Epstein-Barr virus, which only added to the condition's phony reputation. Rather than being considered a potentially disabling illness, it was disregarded as a "yuppie flu" or a fancy name for malingering.

"It's not a surprise that patients are being dismissed because there's already this sort of grandfathered-in sense that fatigue is not real," said Jennifer Frankovich, MD, a pediatric rheumatologist at Stanford University in Palo Alto, California. "I'm sure that's frustrating for them to be tired and then to have the clinician not believe them or dismiss them or think they're making it up. It would be more helpful to the families to say, 'You know what, we don't know, we do not have the answer, and we believe you'."

A Syndrome's Shame

As time passed, patient advocacy groups began pushing back against the negative way the condition was being perceived. This criticism came as organizations like the CDC worked to develop a set of diagnostic criteria that researchers and clinicians dealing with chronic fatigue syndrome could use. With such a heterogeneous group of patients and symptoms, the task was no small challenge. The discussions, which took place over nearly 2 decades, played a key role in helping scientists home in on the single factor that was central to chronic fatigue: postexertional malaise.

"This is quite unique for chronic fatigue syndrome. With other diseases, yes, you may have fatigue as one of the components of the disease, but postexertional fatigue is very specific," said Alain Moreau, PhD, a molecular biologist at the University of Montreal.

Of course, plenty of people have pushed themselves too hard physically and paid the price the next day. But those with chronic fatigue syndrome weren't running marathons. To them, exertion could be anything from getting the mail to reading a book. Nor could the resulting exhaustion be resolved by an afternoon on the couch or a long vacation.

"If they do these activities, they can crash for weeks, even months," Moreau said. It was deep, persistent, and, for 40% of those with chronic fatigue syndrome, disabling. In 2015, a study group from the Institute of Medicine proposed renaming chronic fatigue to "systemic exercise intolerance disease" because of the centrality of this symptom. Although that effort mostly stalled, their report did bring the condition out of its historic place as a scientific backwater. What resulted was an uptick in research on chronic fatigue syndrome, which helped define some of the physiologic issues that either contribute to or result from the condition.

Researchers had long known about the link between infection and fatigue, said Frankovich. Work included mysterious outbreaks like the one in Lake Tahoe and well-documented issues like the wave of encephalitis lethargica (a condition that leaves patients in an almost vegetative state) that followed the 1918 H1N1 influenza pandemic.

"As a clinician, when you see someone who comes in with a chronic infection, they're tired. I think that's why, in the chronic-fatigue world, people are desperately looking for the infection so we can treat it, and maybe these poor suffering people will feel better," Frankovich said. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.

Immunologic Symptoms

Given the close link between a nonspecific viral illness and the onset of symptoms in chronic fatigue syndrome, scientists like Hornig opted to focus on immunologic symptoms. In a 2015 analysis published in Science, Hornig and colleagues showed that immune problems can be found in the earliest stages of chronic fatigue syndrome, and that they change as the illness progresses. Patients who had been sick for less than 3 years showed significant increases in levels of both pro- and anti-inflammatory cytokines, and the factor most strongly correlated to this inability to regulate cytokine levels was the duration of symptoms, not their severity. A series of other studies also revealed problems with regulation of the immune system, although no one could show what might have set these problems in motion.

Other researchers found signs of mitochondrial dysfunction in those with chronic fatigue syndrome. Because mitochondria make energy for cells, it wasn't an intellectual stretch to believe that glitches in this process could contribute to fatigue. As early as 1991, scientists had discovered signs of mitochondrial degeneration in muscle biopsies from people with chronic fatigue syndrome. Subsequent studies showed that those affected by chronic fatigue were missing segments of mitochondrial DNA and had significantly reduced levels of mitochondrial activity. Although exercise normally improves mitochondrial functioning, the opposite appears to happen in chronic fatigue.

To Nath, these dual hypotheses aren't necessarily mutually exclusive. Some studies have hinted that infection with the common human herpesvirus-6 (HHV-6) can lead to an autoimmune condition in which the body makes antibodies against the mitochondria. Mitochondria also play a key role in the ability of the innate immune system to produce interferon and other proinflammatory cytokines. It might also be that the link between immune and mitochondrial problems is more convoluted than originally thought, or that the two systems are affected independent of one another, Nath said.

Finding answers, especially those that could lead to potential treatments, wouldn't be easy, however. In 2016, the NIH launched an in-depth study of a small number of individuals with chronic fatigue, hoping to find clues about what the condition was and how it might be treated.

For scientists like Nath, the NIH study provided a way to get at the underlying biology of chronic fatigue syndrome. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.

Chronic Post-SARS Syndrome

In March 2020, retired physician Harvey Moldofsky, MD, began receiving inquiries about a 2011 study he and his colleague, John Patcai, MD, had published in BMC Neurology about something they dubbed "chronic post-SARS syndrome." The small case–control study, which involved mainly healthcare workers in Toronto, received little attention when it was first published, but with COVID-19, it was suddenly relevant.

Early clusters of similar cases in Miami made local physicians desperate for Moldofsky's expertise. Luckily, he was nearby; he had fled the frigid Canadian winter for the warmth of Sarasota, Florida.

"I had people from various countries around the world writing to me and asking what they should do. And of course I don't have any answers," he said. But the study contained one of the world's only references to the syndrome.

In 2003, a woman arrived in Toronto from Hong Kong. She didn't know it at the time, but her preairport stay at the Hotel Metropole had infected her with the first SARS coronavirus. Her subsequent hospitalization in Toronto sparked a city-wide outbreak of SARS in which 273 people became ill and 44 died. Many of those affected were healthcare workers, including nurses and respiratory therapists. Although most eventually returned to work, a subset couldn't. They complained of energy-sapping fatigue, poor sleep, brain fog, and assorted body aches and pains that persisted for more than 18 months. The aches and pains brought them to the attention of Moldofsky, then director of the Centre for the Study of Pain at the University of Toronto.

His primary interest at the time was fibromyalgia, which caused symptoms similar to those reported by the original SARS long-haulers. Intrigued, Moldofsky agreed to take a look. Their chest x-rays were clear and the nurses showed no signs of lingering viral infection. Moldofsky could see that the nurses were ill and suffering, but no lab tests or anything else could identify what was causing their symptoms.

In 2011, Moldofsky and Patcai found a strong overlap between chronic SARS, fibromyalgia, and chronic fatigue syndrome when they compared 22 patients with long-term SARS issues with 21 who had fibromyalgia. "Their problems are exactly the same. They have strange symptoms and nobody can figure out what they're about. And these symptoms are aches and pains, and they have trouble thinking and concentrating," Moldofsky said. Reports of COVID-19 long-haulers didn't surprise Moldofsky, and he immediately recognized that Nath's intention to follow these patients could provide insights into both fibromyalgia and chronic fatigue syndrome.

That's exactly what Nath is proposing with the two NIH studies. One will focus solely on the neurologic impacts of COVID-19, including stroke, loss of taste and smell, and brain fog. The other will bring patients who have had COVID-19 symptoms for at least 6 months to the NIH Clinical Center for an inpatient stay during which they will undergo detailed physiologic tests.

Scientists around the world are launching their own post-COVID-19 studies. Moreau's group in Montreal has laid the groundwork for such an endeavor, and the CoroNerve group in the United Kingdom is monitoring neurologic complications from the coronavirus. Many of them have the same goals as the NIH studies: to leverage the large number of COVID-19 long-haulers to better understand the earliest stages of postviral syndrome.

"At this juncture, after all the reports that we've seen so far, I think it's very unlikely that there will be no relationship whatsoever between COVID-19 and chronic fatigue syndrome," Hornig said. "I think there certainly will be some, but again, what's the scope, what's the size? And then, of course, even more importantly, if it is happening, what is the mechanism and how is it happening?"

For people like Gage-Witvliet, the answers can't come soon enough. For the first time in more than a decade, the full-time professor of epidemiology didn't prepare to teach this year because she simply can't. It's too taxing for her brain to deal with impromptu student questions. Gage-Witvliet hopes that by sharing her own experiences with post-COVID-19, she can help others.

"In my work, I use data to give a voice to people who don't have a voice," she said. "Now, I am one of those people."

Carrie Arnold is an award-winning public health journalist living in Virginia. Her work has appeared in the New York Times, National Geographic, New Scientist, Scientific American, and Nature, among others. She is currently a Knight Science Journalism fellow at MIT and is working on a book about the multigenerational effects of a Michigan chemical disaster.

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