Feature Story | 7-Nov-2022

Will long COVID research provide answers for poorly understood ailments like chronic fatigue?

By Isabella Backman

Yale University

In 1983, Rivka Solomon was 21 and attending the University of Massachusetts Boston when she and her two roommates came down with infectious mononucleosis, or “mono.” Her roommates recovered within a couple of weeks. She never did.

Following her infection, she could barely get out of bed or stand up to brush her teeth. She was so sick she had to pull out of the university. This went on for a year until she went into what she describes as a “relatively spontaneous quasi-remission.” For several years, she was well enough to go to school, travel, work, and sometimes even exercise. But even during this respite, she constantly dragged a lingering exhaustion with her, and at unpredictable times she would find herself bedridden for days on end, never knowing when the debilitating fatigue would lift.

She was in graduate school in Washington, D.C., studying for her master’s degree when she was hit by a second infection, pneumonia. She pushed through the fatigue to finish her schooling—and then she collapsed. “Nobody told us back then, because nobody knew, that the primary thing you shouldn’t do when you have a post-infectious chronic illness is push through,” Solomon says. After graduation, she “crawled back” home to New England. This was in 1993. She has been in or near bed ever since.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a highly disabling, severe condition that has been largely overlooked and even questioned as an illness by medicine and researchers for decades. But now, following the onset of the COVID-19 pandemic, as many as one in eight infected people, according to Akiko Iwasaki, PhD, Sterling Professor of Immunobiology, are developing “long COVID,” in which symptoms persist for weeks, months, or years post-infection and some are developing symptoms indistinguishable from ME/CFS. As an increasing number of people become debilitated by the post-viral syndrome, researchers such as Iwasaki and Harlan Krumholz, MD, Harold H. Hines, Jr. Professor of Medicine (Cardiology) are striving to uncover the mysteries behind the unrelenting fatigue and numerous other symptoms that seem to linger after COVID infection. They hope to provide answers to not only COVID “long haulers,” but also patients suffering from other poorly understood chronic conditions, including ME/CFS, that have been left unresolved for too long.

“The pandemic has opened the world’s eye to the fact that many chronic illnesses have been largely ignored, dismissed, and ridiculed,” says Iwasaki. “Long COVID has taught the world that these diseases are real, there is a biological basis for them, and we need to study them.”

ME/CFS has an unfortunate name, says Beth Pollack, a research scientist at MIT specializing in chronic diseases including long COVID and ME/CFS, and a scientific collaborator with Iwasaki. It defines the illness by just one of its many symptoms. “There are misconceptions about what fatigue looks like in ME/CFS,” she says. “It’s not the fatigue that someone who is completely healthy might feel if they were just tired. It’s a very different, complex, and much more severe picture in ME/CFS.”

ME/CFS is a “neuroimmune, neuroinflammatory illness that affects numerous organ systems throughout the body, involving dysfunction of the vascular, autonomic, neurological, mitochondrial, metabolic, connective tissue, endocrine, and immune systems,” says Pollack. In addition to its core symptoms, including severe fatigue that is not relieved after sleep, worsening of symptoms post-physical or mental activity, brain fog, and dizziness, patients may also experience aches and pains, difficulty being upright, digestive issues, night sweats, muscle weakness, flu-like symptoms, shortness of breath, and irregular heartbeat. These symptoms existed long before the virus that causes COVID. ME/CFS can have many triggers, including viral and bacterial infections. Some patients develop ME/CFS gradually over months or years. For many others, the symptoms begin much more rapidly.

A hallmark symptom of ME/CFS and now long COVID is post exertional malaise (PEM), which entails an oftentimes severe exacerbation of symptoms after cognitive or physical exertion, which can be delayed. For years, people with ME/CFS were incorrectly advised to do Graded Exercise Therapy (GET), which is no longer recommended. “It can be very harmful to make people with ME/CFS exercise, especially going beyond their energy windows,” says Pollack. “They are physiologically exercise-intolerant and have key dysfunctions in cellular energy production as well as multi-factorial reductions in cardiovascular and cerebral blood flow.” Research using CPET testing and recent molecular research have illuminated possible biomarkers for PEM in ME/CFS.      

The condition ranges in severity. According to Pollack, 61% of people with ME/CFS are bedbound on some days, and about a quarter are bedbound all the time. Three quarters are too sick to work, and only about 5 percent of these individuals will recover. As many as 84 to 97 percent have at least one other comorbid condition. She says that people with ME/CFS commonly develop a group of illnesses including autonomic dysfunction and POTS, mast cell activation syndrome, connective tissue disorders, small fiber neuropathy, autoimmune conditions, and more, and that these illnesses are often interrelated.  “I would propose that given that many of these highly comorbid conditions are also frequently undiagnosed or misdiagnosed, the 84-to-97 percent statistics may perhaps even be underestimates,” says Pollack. The average lifespan of an ME/CFS patient is only 55.9 years, which is over 20 years less than the average U.S. lifespan. And the vast majority of patients—75 to 85 percent—are women.

Historically, many illnesses that impact women were overlooked until a biomarker was discovered or an accurate diagnostic test was developed. “Many women with multiple sclerosis weren’t believed until the MRI machine was invented,” says Pollack. “Fibromyalgia often wasn’t taken seriously, and it turns out that about half of them have small fiber neuropathy—which by the way, is also frequently comorbid with ME/CFS.”

ME/CFS is no exception. It is estimated that more than 90% of individuals with ME/CFS may not have been diagnosed, and Pollack suggests that this is in part due to a lack of general and medical awareness. When awareness of the disease arose in the 1980s, it was dismissed by many as the “yuppie flu.” And for a long time, many providers believed the condition was psychological and could be treated with exercise—which is now known to exacerbate symptoms.

To this day, ME/CFS is the most underfunded illness by disease burden by the National Institutes for Health (NIH), according to an analysis published by IOS Press. A CPT code to diagnose ME/CFS just became available in the U.S. in October 2022, and beforehand, doctors had to use the code for chronic fatigue. Because many conditions have the symptom of chronic or persistent fatigue, and this is not the same thing as ME/CFS, this new CPT code will allow for better research, Pollack says.

“It’s important to ask, ‘Why hasn’t more research funding historically been allocated to develop appropriate testing and treatments, and to research biomarkers of ME/CFS?’” she says.

There is no universal definition for long COVID. The Centers for Disease Control and Prevention (CDC) defines long COVID as symptoms persisting a minimum of 4 weeks post-infection. The World Health Organization (WHO) describes   it as unexplained symptoms beginning within three months after being infected with COVID that last at least 2 months. These symptoms may include unrelenting fatigue as well as a range of neuroimmune symptoms. Pollack emphasized that for around half of people with long COVID, their condition also meets the diagnostic criteria for ME/CFS. With nearly 10 percent of those infected with COVID developing long COVID and only a handful of ME/CFS specialists in the country, the already woefully under-resourced medical system is not set up to accommodate this new wave of patients.

At Yale School of Medicine, Iwasaki and Krumholz are striving to figure out how infectious diseases can trigger chronic illnesses like ME/CFS. After the onset of COVID-19 in 2020, many providers and researchers believed the infections were acute. Now, says Iwasaki, the definitions of acute and chronic are becoming “a little bit blurred.” Autopsy samples from individuals who had acquired COVID months before revealed evidence of SARS-CoV-2 in different tissues, suggesting that effects of the virus had been ongoing. “This so-called acute infection may not be that acute,” says Iwasaki.

They have several hypotheses for why long COVID may be causing lingering symptoms. First, there may be a level of virus remaining that is triggering inflammation beyond COVID’s acute phase. Second, the acute infection may trigger autoreactive T and B cells that are creating an autoimmune response. Third, COVID-19 may create a dysbiosis (imbalance) within the gut microbiome that is creating long COVID symptoms or reactivating latent viral infections. Or, SARS-CoV-2 may be causing irreparable tissue damage leading to lingering symptoms such as shortness of breath. It is likely a combination of all these things. “When we say long COVID, there are probably four or five diseases, if not more, under that umbrella term,” says Krumholz.

Long COVID is not the first post-acute infection syndrome. Other infections such as Ebola, Epstein-Barr, West Nile virus, and Lyme disease are also known to cause a set of lingering symptoms including fatigue and post-exertional malaise—conditions that are known all too well by ME/CFS patients.

“Having adequate funding to study these illnesses would have helped us be better prepared for the pandemic and long COVID,” says Pollack. “But now, we have to look forward to the future.”

Iwasaki believes that the growing research around long COVID could also shine light on the mechanisms behind other chronic illnesses like ME/CFS. In her own research, she plans to compare the immune phenotypes of patients who acquired ME/CFS from an unknown infection—in most cases, individuals don’t know what infection triggered their disease—and those struggling after Lyme disease, to those of COVID long haulers. “We want to understand what’s common and what’s different and how to illuminate the disease pathogenesis,” she says.

As growing numbers of long haulers continue to suffer, Krumholz sees the urgency for bringing patients into clinical trials in large numbers and running tests and evaluations rapidly. He and Iwasaki hope to create an approach that optimizes factors including the enrollment of patients in the United States in trials, collection of blood and other samples in a manner convenient to participants, the delivery of questionnaires that are easy to fill out, and more. “All of these things can easily be transferred and used for the research into other conditions,” he says.

The pandemic encouraged Krumholz, a cardiologist and physician-scientist, to pair up with Iwasaki, a basic researcher in immunobiology. The two recently launched the Yale LISTEN Study, which according to their website, strives to learn more about “long COVID, post-vaccine adverse events, and the corresponding immune responses.” Although they come from vastly different worlds, they have learned to build upon each other’s expertise to confront the challenges of the pandemic. Because the symptoms of poorly understood chronic illnesses like long COVID or ME/CFS are so widespread, they often fly under the radar of many physicians, who tend to be hyper-focused on their area of expertise. These new alliances may provide the more holistic view needed to better understand chronic illness.

Outside of Yale, other multidisciplinary research studies around the country are being launched to better understand chronic illness. Pollack leads and is building a new research unit at MIT studying the overlapping pathomechanisms and comorbidities among long COVID, ME/CFS, and a group of related illnesses. She is also involved with MAESTRO, a multi-cohort long COVID and chronic Lyme disease research study by the Tal Research Group at MIT, focused on deep immune profiling, neuroinflammation, and many different potential biomarkers. Other researchers are exploring the vascular pathologies of long COVID and ME/CFS, including clotting, hypercoagulation, and vascular-related autonomic dysfunction. There has also been increased interest in researching the role of mitochondrial function in chronic illness, including at Harvard University.

“The wind is shifting already,” says Iwasaki. “People realize that these diseases have been ignored and that it is time to act. We cannot ignore these conditions anymore.”

“No one wanted the pandemic, but sometimes a jolt to the system can create innovation in ways that wouldn’t have occurred otherwise,” says Krumholz.

Pollack foresees a “new era” for chronic disease research, but also emphasizes the importance of building upon previous research on ME/CFS and other “invisible” illnesses and not letting valuable historical research be overlooked or forgotten. She looks forward to a new chapter of more deeply involving expert patients in biomedical research, something that she believes will benefit the entire field.

Recently, Solomon attended a webinar where the researchers described long COVID as “new and novel.” She felt disappointed. The lack of understanding of the history of post-infectious chronic illness among the research community is still evident.

But in some ways, she feels hopeful. “It is my hope that long COVID researchers will connect the dots and see how ME and long COVID are pretty much the same thing,” she says. “If they do research into things like dysautonomia, hormones, or PEM, that should in the end help all of us with ME/CFS too.”

“We hope long COVID research will offer some answers for ME/CFS, too,” adds Solomon’s mother, Bobbi Ausubel. “And we hope U.S. federal health agencies will finally step up to the plate and fully fund ME/CFS researchers, now that we understand how closely connected most post-infectious chronic illnesses are, such as long COVID and ME/CFS. No mother should have to wait decades for a treatment to help their daughter. Right now, there is not a single FDA-approved treatment for ME/CFS. As a mother, it is hard to watch your daughter struggle for so long.”

As post-viral exhaustion lays its grasp on growing numbers of people, there have been more and more calls for the NIH to increase its modest funding for ME/CFS. Solomon and her mother hope they listen.

When asked if he feels that long COVID will illuminate treatment for other illnesses, Krumholz says “there’s not any doubt about it.”

“I hope we’ll be able to relieve the suffering for long haulers, but our work is going to provide insights that we can quickly transfer to other poorly defined illnesses,” he continues. “Through our combination of deep clinical science and expertise with laboratory science, we can begin to make progress where we’ve been stymied in the past.”

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