Most studies examining the effects of activity-based interventions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have not enrolled people who have the condition as it's currently defined, requiring the core symptom of post-exertional malaise (PEM), a new analysis found.
Diagnostic criteria for the illness have evolved from those defining "CFS" as simply 6 months of otherwise unexplained fatigue (1991 Oxford), to later including PEM as a possible symptom of "CFS" but not requiring it to make the diagnosis (1994 Fukuda), to more specific criteria for "ME" or "ME/CFS" (Canadian Consensus, International Consensus, 2015 Institute of Medicine, 2021 National Institute for Health and Care Excellence) that require the presence of PEM -- along with other features such as profound chronic fatigue and unrefreshing sleep -- to make the diagnosis.
Studies using older "CFS" criteria have produced misleading results with regard to exercise and should not be applied to people whose condition is defined by PEM, a worsening of multiple symptoms with exertion, Marjon E. A. Wormgoor, MS, a researcher from the Division of Mental Health and Addiction, Vestfold Hospital Trust, Tønsberg, Norway, said at International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFS/ME) 2025 virtual meeting.
"We face a mismatch around physical activity between established medical practice and what the evidence actually shows. For decades, medicine has worked from the idea that physical activity promotes health and recovery...This underlying idea continues to underpin many activity-based interventions for people with ME, based on the expectation that more activity will lead to improvement. However, this assumption directly conflicts with the core feature of ME, exertion intolerance, or post-exertional malaise," Wormgoor said in her introduction.
In fact, PEM has been well-documented in ME/CFS research showing abnormal biological responses after exertion as assessed by cardiopulmonary exercise testing (CPET; see here and here) and by surveys in which patients consistently name graded exercise as among the interventions that worsened their symptoms. In contrast, pacing their activity levels to conserve limited energy stores is named among the most helpful practices among people with ME/CFS, including those with long COVID who meet ME/CFS criteria.
"Since clinical practice is meant to be evidence-based, we have to ask: Does clinical trial evidence truly support activity-based interventions for people with ME, or have they been framed by prevailing assumptions that physical activity promotes recovery?" Wormgoor said.
Clinical practice guidelines in the US and the UK no longer recommend graded exercise for treating ME/CFS, but many clinicians still prescribe it.
Asked to comment, IACFS/ME board member and conference co-organizer Luis Nacul, MD, PhD, told Medscape Medical News, "That's a huge problem...in research it's very important to have the case definitions well defined, and should refer to what research is intended to capture. Otherwise, the conclusions will be biased, and this may cause harm to patients, or at least may delay progress in science and waste resources. At worst, it may actually impact patients in a very, very dangerous way."
The problem with using the broader "CFS" definitions, said Nacul, clinical associate professor at both the London School of Hygiene and Tropical Medicine in London, England, and at the University of British Columbia, Vancouver, British Columbia, Canada, is that the study samples "will include cases with many other causes of fatigue, including other organic disease or depression or mental health illnesses. This is not good for research. You want purer samples."
The Literature Doesn't Reflect the Relevant Condition
At the IACFS/ME meeting, Wormgoor presented an update to her 2021 systematic review paper examining randomized clinical trials of physical activity interventions for adults diagnosed with CFS or ME criteria, published between 2000 and 2024. The interventions include rehabilitation modalities, exercise-based programs including graded exercise, and mind-body exercises such as yoga or qigong.
Of the 17 trials meeting inclusion criteria, three used "CFS" definitions that didn't include PEM at all, 13 used criteria in which PEM was an optional criterion, and only one used a definition that required PEM, although there was no mention of PEM in that paper. Most used subjective outcome measures such as fatigue scales or physical function surveys, while objective measures were "rare and inconsistent," she said.
While some of the studies found positive short-term improvements, results were generally inconsistent. Moreover, Wormgoor pointed out that most of the studies reflected several other sources of bias, such as inadequate reporting of adverse events, treatment compliance, or dropout rates. Moreover, study participants generally had mild diseases because those more severely affected would not be able to participate.
And none of the studies assessed PEM. "Many of the applied instruments were not designed to capture PEM at all...still, the evidence is presented as relevant for ME," she noted.
And the same issue is likely affecting long COVID research as well, Todd Davenport, PT, DPT, PhD, professor and chair of the Department of Physical Therapy at the University of the Pacific, Stockton, California, told Medscape Medical News. "The observation of ME in long COVID has brought renewed importance to the need to use specific case definition criteria in intervention studies. My preliminary work with students has identified a similar trend in long COVID exercise studies as Wormgoor has found in ME/CFS. The mixing of participants who may and may not respond normally to physical loading is probably also now confounding results in long COVID literature."
Studies Involving Individuals With PEM Show Biological Abnormalities
Several other researchers at the conference presented data from their studies using methods that have become standard among those in the field: recruitment of participants who meet ME/CFS criteria requiring PEM and also using sedentary age- and sex-matched control individuals to ensure that any detected abnormalities are not due to deconditioning from inactivity. These studies aim to better understand the pathophysiology of ME/CFS, as well as to identify biomarkers to improve diagnosis and point to drug targets.
Among these, a study from the University of Edinburgh, Scotland, of 1455 ME/CFS cases and 131,303 control individuals from the UK Biobank identified and subsequently replicated biomarkers in people with ME/CFS associated with chronic inflammation, insulin resistance, and liver disease that were determined not to result from variations in physical activity.
In another study, from Cornell University, Ithaca, New York, cell-free RNA signature profiles in 93 people with ME and 75 healthy sedentary control individuals distinguished the two groups with high accuracy, while biological network analysis identified immune dysfunction in ME with signatures of cytokine signaling and T-cell exhaustion.
A third study, also from Cornell, researchers conducted an integrative analysis of the plasma proteome and metabolome before and after each of 2 days performing CPET in 60 patients with ME/CFS compared with 43 healthy sedentary controls and identified 26 potential biomarkers that could distinguish between the two groups. The ME/CFS group had significant ongoing dysregulation in both the proteome and metabolome.
New Research Definition Under Development
Even among the studies that have recruited individuals with PEM, there is still variation in case definitions. Now, under the leadership of Leonard A. Jason, PhD, the IACFS/ME is working on developing a new consensus research case definition for ME/CFS -- which would likely be narrower than the clinical diagnostic criteria -- with the aim of better standardization across studies. This definition will include PEM, cognitive impairment, fatigue, and unrefreshing sleep among other criteria, and will likely specify other aspects such as illness severity, duration, course, and comorbidities.
Jason, director of the Center for Community Research and professor of psychology at DePaul University, Chicago, told Medscape Medical News, "The fact that not all researchers include PEM is part of the problem as PEM is the central defining symptom of ME/CFS. So a research case definition helps with clinical practice as the findings from such a set of criteria leads to better science, which will then get more funds for research, even from the drug companies, to pursue promising directions...If your research sample includes a mix of people with different conditions, it becomes harder to find the markers that the patients and researchers are hoping to find. Without them, the condition will continue to be stigmatized and that is not a good thing for patients."
Clinically, PEM Is an Important Aspect for Discussion
Clinically, in addition to asking patients how they typically feel in the 24-48 hours post-exertion, several tools are available to assess PEM. Jason recommends the DePaul Symptom Questionnaire -- Post-Exertional Malaise (DSQ-PEM) that he developed. Wormgoor uses the Assessing Functional Capacity in Myalgic Encephalopathy/Chronic Fatigue Syndrome (FUNCAP), developed by her Norwegian colleagues.
In a 2023 paper analyzing two patient surveys, Wormgoor and colleagues found that PEM is still infrequently acknowledged in specialist healthcare for ME/CFS patients in Norway. They also found, she told Medscape Medical News, that "not addressing PEM significantly increased the likelihood of health and functional decline following intervention, and was strongly associated with lower perceived care quality, satisfaction, and benefit."
Wormgoor, Jason, and Davenport reported having no disclosures. Nacul reported receiving funding from the Canadian Institutes of Health Research.
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR's Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.