American researchers have found notable differences between the immune systems and other physiological functions of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and those of healthy patients.
Their findings, they say, confirm that the condition is not psychological but is definitely biological – and could have implications for treatment of long Covid.
Seven years ago, the National Institutes of Health (NIH) began a study of patients with ME/CFS, signing up a group of participants for a series of tests and evaluations of their blood, bodies and brains.
The findings, recently published in Nature Communications, showed significant physiological differences in the immune system, cardio-respiratory function, gut microbiome and brain activity of the ME/CFS patients compared with a group of 21 healthy study participants.
Medical experts said that even though the study was a snapshot of a small number of patients, it was valuable, partly because ME/CFS has long been dismissed or misdiagnosed.
“The findings confirm that it’s biological, not psychological,” said Dr Avindra Nath, chief of infections of the nervous system at the National Institute of Neurological Disorders and Stroke, who led the study.
The New York Times reports that the findings may also have implications for patients with long Covid, which often includes symptoms similar or identical to those of ME/CFS. Though the study participants were recruited before the pandemic, all had a type of ME/CFS that is preceded by an infection, just as long Covid is preceded by a coronavirus infection.
“Whatever we learn from ME/CFS will benefit long Covid patients, and whatever we learn from long Covid will benefit ME/CFS patients, I think,” said Nath, adding that the infections experienced by the patients in the study varied. (None had Lyme disease; one was C. diff.)
The immune system differences were among the clearest findings, said Dr Anthony Komaroff, a professor of medicine at Harvard Medical School who was not involved in the research but served as a reviewer of the study for the journal. “They found chronic activation of the immune system, as if it were engaged in a long war against a foreign microbe, a war it could not completely win and therefore had to continue fighting.”
Nath said his theory is that, in both long Covid and post-infectious ME/CFS, “either you have bits and pieces of that pathogen sticking around and driving this thing or the pathogen is gone… but whatever it did to the immune system, it just never settled down again”.
Another distinctive finding was that, when participants were asked to perform tasks measuring their grip strength, a part of their brain involved in co-ordinating and directing actions showed decreased activation, while, in healthy people, it showed increased activation.
“That brain area, the right temporal-parietal junction, is involved in telling the legs to move, telling the mouth to open and eat – it sort of says ‘do something’,” Komaroff said. “When it doesn’t light up properly, it’s harder to get the body to make that effort.”
He said the NHI researchers speculate that the chronic immune stimulation they found, and the changes in the gut microbiome, could lead to these brain changes, which then leads to symptoms.
Experts cautioned that the results of the small study may not reflect the experience of the many people who have ME/CFS.
The condition can also develop in people who have not experienced infections. And while ME/CFS is often characterised by severe energy depletion after physical or cognitive exertion (a phenomenon called post-exertional malaise), the study participants had to be functional enough to undergo intense evaluation during days of visits to the NIH in Maryland.
“They selected rather healthy patients,” said Dr Carmen Scheibenbogen, a professor of immunology at the Institute for Medical Immunology at Charité hospital in Berlin, who was not involved in the study.
“I think there are a lot of interesting findings, it’s just disappointing, because that was such a major approach and they selected patients who are not very representative.”
Beth Pollack, a research scientist at the Massachusetts Institute of Technology, noted that, in the years after participating, four of the 17 patients “spontaneously recovered” from the condition, which she said is not typical of ME/CFS.
Both she and Scheibenbogen also said the study did not find some medical signatures of the condition that had been documented by other research. For example, it did not find that patients performed more poorly on cognitive tests or that they had neuro-inflammation.
“These are well-established pathologies and central to ME/CFS,” Pollack said, “so this did not address everything, and it contradicted some things that we know.”
Scheibenbogen said the most important findings are that the condition is driven by immune system dysregulation, and that the researchers clearly state it is a physiological condition, “not a psychosomatic disease”.
Experts said the study, which is the NIH’s first detailed look at ME/CFS, should be considered only one step in understanding the condition, its severity and potential remedies. “We must advance the field towards research on treatment,” Pollack said.
Jennifer Caldwell (56) was active and energetic, working two jobs and taking care of her daughter and her parents, when she developed a bacterial infection, followed by intense light-headedness, fatigue and memory problems.
That was nearly a decade ago, and she has since struggled with ME/CFS. Caldwell went from being able to ski, dance and work two jobs as a clinical research co-ordinator and a caterer, to needing to stay in bed most of every day.
She became one of the participants in the NIH study.
For the past 10 years, “I haven’t been right … and I haven’t worked a day since,” said Caldwell, whose symptoms include severe dizziness whenever her legs are not elevated.
The condition has also “messed me up cognitively”.
“I can't read something and comprehend it well, I can’t remember new things. It’s like being in a limbo state. I describe it as lost in limbo.”
She said some aspects of the experience as a study participant were sobering, like when she scored a 15 on a 100-point scale of physical functioning, and a 6.25 on a 100-point “vitality” scale measuring energy level, fatigue and feelings of well-being.
Her main hope for the study, she said, is that it will encourage doctors and others to recognise ME/CFS and take it seriously.
“For so long I’ve been dismissed, invalidated, belittled…so the validation is huge for me.”
Study details
Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome
Brian Walitt, Komudi Singh, Avindra Nath, et al.
Published in Nature Communications on 21 February 2024
Abstract
Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.
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