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Long COVID Dispatches with Lisa Sanders

Long COVID, ME/CFS and the Importance of Studying Infection-Associated Illnesses

BY OSMAN MONEER May 13, 2024

Research on Long COVID may also shine light on the underlying causes of myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS.

The COVID-19 pandemic posed many unprecedented global challenges. But as reports of Long COVID cases grew, there were some patients for whom the persistent symptoms of the post-viral syndrome felt familiar.

Even before COVID-19 spread across the planet, patients were presenting with similar constellations of symptoms following other infections, which doctors and researchers collectively referred to as infection-associated chronic illnesses or post-acute infection syndromes. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a neuroinflammatory, neuroimmune illness most commonly triggered by infection, such as Epstein-Barr virus, though patients have reported other triggers as well, such as physical accidents and environmental exposures.

ME/CFS is characterized by prolonged and severe fatigue, and by symptoms that worsen after physical or cognitive exertion (known as post-exertional malaise, or PEM), sleep disturbances, brain fog/difficulty thinking, dizziness and orthostatic intolerance (the medical term for when standing up causes symptoms), headaches, muscle weakness and pain, and more.

To Beth Pollack, an ME/CFS expert and research scientist at MIT who studies infection-associated chronic illnesses, ME/CFS is a chronic illness that affects multiple systems in the body. “Research has shown that ME/CFS involves dysfunction of the immune and nervous systems, as well as cardiovascular, connective tissue, gastrointestinal, metabolic, and mitochondrial dysfunction,” she says.

What is ME/CFS?

ME/CFS is a severe, disabling, and life-altering disease: 75% of ME/CFS patients are too ill to work, and a quarter of patients are unable to leave their homes or, in some cases, their beds. Some physicians caring for ME/CFS patients say it’s one of the most disabling illnesses they've ever seen. According to the late William Reeves, MD, former head of Viral Diseases at the Centers for Disease Control and Prevention (CDC), “The level of functional impairment in people who suffer from CFS is comparable to multiple sclerosis, AIDS, end-stage renal failure and chronic obstructive pulmonary disease.”

Dr. Deborah F.* agrees with that assessment. She is a family physician who, like so many doctors, had COVID-19 early in the pandemic, in March 2020, before anyone really understood what it was. As a then-33-year-old “super healthy, physically active, and athletic person,” she believed that she’d recover from COVID quickly and return to seeing patients. However, she didn’t recover, and four years later she is still not well enough to return to her job. She’s tried many times but hasn't been able to do the work. Too often, she experiences severe, debilitating symptoms within an hour of work. She has had to accept that at this time she is still physically unable to work, even though she misses practicing medicine, which she loved. “I feel like I’m trying to run on an empty gas tank,” Dr. F. says. No matter how much she rests, the fatigue never really leaves her.

“I went through high school, college, medical school, and family medicine residency, doing intense, 80-plus-hour work weeks during residency,” she explains. “I always worked hard and was a total over-achiever. I thought I knew what it meant to get ‘tired’ back then, but this is so much more than that. I was used to the kind of fatigue where you can take a power nap or get a cup of coffee, and then power through. But ME/CFS isn’t like that. The fatigue drops you where you are. There is usually no pushing through. It’s so much worse. You just can’t function. And you have no idea how long the fatigue will last.”

Studies over the last few years have found that about half of people with Long COVID meet diagnostic criteria for ME/CFS, and the prevalence of ME/CFS has been growing as a result of the pandemic and Long COVID. Recent estimates suggest that there may be 3.3 million Americans living with ME/CFS, possibly growing to 5-9 million as a result of the pandemic. Findings from ME/CFS research have helped inform research directions for Long COVID.

How similar are Long COVID and ME/CFS?

Numerous studies have revealed a significant overlap in symptoms reported by patients with Long COVID and ME/CFS. For instance, studies comparing patients found that both groups experienced orthostatic intolerance and autonomic dysfunction, in which just standing upright induces symptoms such as dizziness or lightheadedness.

However, there are some distinctions. Long COVID is defined as symptoms persisting a minimum of four weeks post-infection, according to the CDC. It is heterogenous, with over 200 symptoms. While a subset of patients have ME/CFS, many do not. A 2022 NIH study, led by researchers at Weill Cornell Medicine, identified four major subgroups of the disease. One subgroup associated with predominantly neurological symptoms may be more aligned with ME/CFS. Many Long COVID patients experience decreased smell and taste and respiratory issues, which are not as common in ME/CFS.

How are ME/CFS and Long COVID diagnosed?

Doctors typically identify diseases by using a combination of lab tests and a pattern of unique symptoms. But given how varied symptoms can be, along with the absence of specific diagnostic lab tests, both Long COVID and ME/CFS can be difficult to diagnose. Both diseases are frequently seen as diagnoses of exclusion (meaning the diagnosis is made after ruling out other conditions that can cause similar symptoms), contributing to delays in diagnosis and misdiagnosis. Despite substantial knowledge and documentation of disease pathologies, researchers are still studying and trying to understand the complex mechanisms underlying these diseases.

What’s next for ME/CFS and Long COVID?

What’s next for these illnesses? Historically, ME/CFS has been underfunded relative to its disease burden. More research is critical to better understand the underlying mechanisms of both Long COVID and ME/CFS and to inform future clinical trials.

Importantly, according to Pollack, ME/CFS and Long COVID commonly co-occur with a group of other overlapping conditions, including postural orthostatic tachycardia syndrome (POTS), small fiber neuropathy, mast cell activation disorders, connective tissue disorders, and reproductive health conditions. Pollack recommends that both researchers and clinicians screen for co-occurring diseases in those diagnosed with ME/CFS or Long COVID.

“Unfortunately, the most severe and complex patients often fall through the cracks of both clinical care and research,” says Pollack. “We need to include severe patient cohorts in research, even if it means visiting them at home while they are in bed.”

Ongoing research, including work at Yale by the lab of Akiko Iwasaki, PhD, Sterling Professor of Immunobiology, seeks to clarify the basis for Long COVID and to better understand its relationship with ME/CFS. Iwasaki’s lab and MIT’s Tal Research Group, where Pollack works, are collaborating in their efforts to understand these diseases. At MIT, the Tal Research Group, led by Michal Tal, launched the MAESTRO study on Long COVID and chronic Lyme disease, and hopes to add an ME/CFS cohort. MAESTRO aims to identify biomarkers and mechanisms of illness, increase understanding of the overlaps among these illnesses, and predict who develops chronic illness after infection. In addition to the MIT-Yale collaboration, the Iwasaki lab is collaborating with the team of David Putrino, PhD, at the Mount Sinai School of Medicine, to enroll pre-pandemic ME/CFS patients to conduct deep immune phenotyping.

Pollack is hopeful that we are entering a new era of chronic illness research. There has been a series of conferences to explore the pathophysiology of Long COVID and ME/CFS, including two at the National Academies of Sciences, Engineering, and Medicine; a Keystone conference; an ECHO series, led by the Bateman Horne Center; and a series of NIH webinars bringing together world experts to summarize ME/CFS research.

Pollack chairs an NIH subgroup on “less studied pathologies” in ME/CFS, and she organized and led a four-hour NIH research webinar in January 2024 on understudied topics in the disease that greatly impact patients—the first event of its kind in the field. She encourages clinicians, researchers, students, and patients to watch some of the eight NIH Research Roadmap webinars, as they cover many ME/CFS subtopics in-depth, reviewing the current state and next steps for research.

“We are thinking about how we advance the field toward clinical trials and therapeutics,” says Pollack. “These illnesses urgently need effective treatments. We also need deep phenotyping and mechanistic research that helps us identify subsets most likely to benefit from certain treatments. When appropriate, cross-illness research such as clinical studies and clinical trials with ME/CFS and Long COVID comparator cohorts, or other cohorts like POTS, are important to consider.”

*Not her real name.

Osman Moneer is an MD candidate at Yale School of Medicine

The last word from Lisa Sanders, MD:

Fatigue is common after an illness. Recovery does take time. But ME/CFS is a whole different level of fatigue. Dr. F. is a patient of mine at the Yale New Haven Long COVID Multidisciplinary Care Center, and I’ve watched her struggle to recapture even a part of the life she used to have. She has trouble taking care of herself and when she’s really bad off she goes home to live with her parents. She sleeps 12 to 16 hours at night and naps during the day—every day. And, while she has a day when she can function every now and then, she still has to be careful. If she does too much, she can “crash,” as she calls it—and then is unable to even get out of bed for a day or two or three or four. “With Long COVID, it’s so unpredictable how my body will respond,” she explains. “One day I can do something. But when I try it another day, I will crash.”

The frustration for Dr. F. and for all the doctors who participate in her care is that we don’t know enough about this disease to help her. And so far, nothing we have tried has helped. She keeps trying. We keep trying. Right now, it’s all we can do.

If you’d like to share your experience with Long COVID for possible use in a future post (under a pseudonym), write to us at:

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