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

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

Yale Medicine – Lisa Sanders, MD

Nothing new in this fairly comprehensive US review of the clinical and pathological overlaps between Long Covid and ME/CFS

However, it's good to see that these medics from Yale are acknowledging that these overlaps exist and that a significant proportion of people with Long Covid meet diagnostic criteria for ME/CFS

Dr C Shepherd, Hon. Medical Adviser for the ME Association


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.

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?

Some physicians caring for ME/CFS patients say it’s one of the most disabling illnesses they've ever seen

“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.”

William Reeves, MD, former head of Viral Diseases at the Centers for Disease Control and Prevention (CDC)

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.

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.

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 conditionsPollack 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. We need to include severe patient cohorts in research, even if it means visiting them at home while they are in bed.”

Beth Pollack, ME/CFS expert and research scientist at MIT

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

Pollack is hopeful that we are entering a new era of chronic illness 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.”

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