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Two physicians who treat patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have issued a statement expressing gratitude for the recent National Institutes of Health's "deep phenotyping" study of the condition that identified several distinct biologic abnormalities but also criticized some aspects of the study and the way the findings were reported.

One of the statement's authors, Lucinda Bateman, MD, founder and medical director of the Bateman Horne Clinic (BHC) in Salt Lake City, Utah, was an independent case adjudicator for the study but had no role in the data analysis or the publication. The other statement author, Brayden Yellman, MD, is a BHC medical provider.

The two issued the statement in response to "a whirlwind of impassioned commentary" about the study on social media and elsewhere, much of it around the use of the term "effort preference" to describe results from one of the study tests and the lack of focus on the hallmark ME/CFS symptom post-exertional malaise (PEM). All 17 of the study patients experienced PEM, a core criterion of the 2015 Institute of Medicine's ME/CFS case definition.

"We are grateful to the volunteers and research staff whose dedication facilitated data collection and to the patients who risked their energy envelopes, their time, and their health to serve this comprehensive study, which will serve as a foundation for future studies…But no study is perfect," Bateman and Yellman wrote.

One way the study "fell short," they said, was by "not including enough patients who are moderately to severely ill. That happens frequently in ME/CFS research and was probably amplified by the travel, rigor, and duration of the study." Moreover, they pointed out that the investigators had intended for the study to be larger, but the COVID-19 pandemic interfered with recruitment.

However, they also noted that the study's inclusion of only patients with postinfectious ME/CFS for less than 5 years' duration may help explain why the findings "don't fully reflect the larger population of chronically ill people with ME/CFS."

In an interview with Medscape Medical News prior to the study's publication, lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at the National Institute of Neurological Disorders and Stroke (NINDS), said that the selection of both recent-onset patients and those who were less severely ill was done in part to avoid the confounding factor of deconditioning.

"We were very careful not to take deconditioned patients. That doesn't mean that small amounts of deconditioning didn't take place, but I don't think it can all be explained by that. For example, we found functional brain abnormality that cannot be explained by deconditioning. And then there were some immune abnormalities. We found naive T cells and B cells were activated, and the anti-programmed death-1 level was elevated. So, there were a number of findings that I think cannot be explained by deconditioning."

PEM Underlies the Condition, But Language Is Limiting

Bateman and Yellman, along with some patients with ME/CFS on social media, took issue with the study report's use of the term "effort preference" to describe results on the Effort-Expenditure for Rewards Task, which is used to assess effort, task-related fatigue, and reward sensitivity. According to the paper, "given equal levels and probabilities of reward, [healthy volunteers] chose more hard tasks" than did the participants with postinfectious ME/CFS (odds ratio, 1.65; P = .04).

Bateman and Yellman wrote, "We were particularly dismayed by use of the term 'effort preference' as an explanation for the origin of fatigue when the authors subsequently go on to suggest that their data and other published data substantiate dysregulation of autonomic nervous system functioning and changes in metabolic pathways that could more readily be implicated, if not fully understood, in contributing to overall fatigue."

Whitney Dafoe, a patient bedbound with very severe ME/CFS in Stanford, California, put it this way on the social media platform X: "Describing ME/CFS patients as having 'Altered Effort Preference' is such bullshit. Would you resist if you were pushed next to a cliff with a long drop? Is that 'Effort Preference'? Or are you reacting to something that would hurt you? It's that simple."

According to Nath, "we battled around with ourselves about what is the right term to use. The problem is that it's a subjective sensation…And even the patients who experience it use a variety of different terms to describe it."

But, Nath said, the way he interprets the symptom based on what patients have said is that it's akin to having the flu and not wanting to get out of bed. "It's not like you're not capable of doing it, but your body tells you don't do it…Your body just wants to fight the infection. So, the way I understand their symptoms, that's what's happening to these individuals. They got the infection, their body kind of shut down, and then it never recovered…And we did find some of that reflected in their immune systems."

Another complaint of Bateman and Yellman's and echoed on social media pertained to the use of just 1 day of cardiopulmonary exercise testing (CPET) rather than 2, which is how some prior studies have objectively demonstrated the "post-exertional malaise" phenomenon. "As we all know, [post exertional malaise] is a distinct and debilitating physiological phenomenon that differentiates ME/CFS from other fatiguing illnesses and that can be measured (approximately) via 2-day CPET testing," the two physicians noted.

Regarding that, Nath had said, "the problem was these patients can't tolerate it. With the testing we did, it took them days to recover after…but we did see a lot of abnormalities on [1-day] CPET."

Nonetheless, 'Significant Strides' and Optimism for the Future

On the positive side, Bateman and Yellman did point out that a National Institutes of Health (NIH)-funded study on ME/CFS is itself one of several signs of progress in the way NIH approaches the condition.

"Over the past decade, we've witnessed significant strides, including the establishment of a dedicated NIH home for ME/CFS within NINDS, two evidence-based literature reviews, a new clinical case definition, 5 years of extramural funding for collaborative research centers, a heightened recognition of patient experiences, and the integration of ME/CFS knowledge and language across [the Department of Health and Human Services]."

They add that the COVID-19 pandemic "has significantly augmented our understanding of post-viral syndromes compared to almost a decade ago when the ME/CFS inpatient protocol was conceived."

And they cited another "exciting" NIH initiative, the NIH ME/CFS Research Roadmap. "This is a year-long project to bring together teams of scientists, clinicians, and people with lived experience, to brainstorm the most important aspects of ME/CFS, review the literature, and recommend what might be the 'roadmap' ahead for ME/CFS research, especially research that can lead to effective treatments."

Bateman and Yellman had no relevant disclosures. Nath is an NIH employee with no further disclosures.