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

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.

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.

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.

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.

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.

Read other installments of Long COVID Dispatches here.

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: LongCovidDispatches@yale.edu

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