Jennifer Caldwell was active and energetic, working two jobs and taking care of her daughter and her parents, when she developed a bacterial infection that was followed by intense lightheadedness, fatigue and memory problems.
That was nearly a decade ago, and she has since struggled with the condition known as myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS. Ms. Caldwell, 56, of Hillsborough, N.C., said she went from being able to ski, dance and work two jobs as a clinical research coordinator and a caterer to needing to stay in bed most of every day.
“I haven’t been right since, and I haven’t worked a day since,” said Ms. Caldwell, whose symptoms include severe dizziness whenever her legs are not elevated.
The condition has also “messed me up cognitively,” she said. “I can’t read something and comprehend it very well at all, I can’t remember new things. It’s kind of like being in a limbo state. That’s how I describe it, lost in limbo.”
Seven years ago, the National Institutes of Health began a study of patients with ME/CFS, and Ms. Caldwell became one of 17 participants who engaged in a series of tests and evaluations of their blood, bodies and brains.
Findings from the study, which was published on Wednesday in the journal Nature Communications, showed notable 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, the chief of infections of the nervous system at the National Institute of Neurological Disorders and Stroke, who led the study.
The findings may have implications for patients with long Covid, which often includes symptoms that are 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 Dr. Nath, who said the infections experienced by the patients in the study varied. (None had Lyme disease; Ms. Caldwell’s infection 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 the immune system was engaged in a long war against a foreign microbe, a war it could not completely win and therefore had to continue fighting,” he said.
Dr. 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 coordinating 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,” Dr. Komaroff said. “When it doesn’t light up properly, it’s harder to get the body to make that effort,” he continued, adding that the N.I.H. researchers “speculate that the chronic immune stimulation that they found and the changes in the gut microbiome that they found 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 characterized 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 N.I.H. 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 which 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 Dr. Scheibenbogen also pointed out that the study did not find some medical signatures of the condition that have been documented by other research. For example, it did not find that patients performed more poorly on cognitive tests or that they had neuroinflammation.
“These are well-established pathologies and really central to ME/CFS,” Ms. Pollack said, adding “so this did not address everything, and it contradicted some things that we know.”
Dr. 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 N.I.H’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,” Ms. Pollack said.
For Ms. Caldwell, 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 recognize ME/CFS and take it seriously.
“We’re kind of like at the point of trying to get understood, so this study is a big deal,” she said. “For so long I’ve been gaslit, dismissed, invalidated, belittled,” she added, “so the validation is huge for me.”