Study of patients with chronic fatigue disorder may provide clues to long Covid

Jennifer Caldwell was active and energetic, working two jobs and caring for her daughter and her parents, when she developed a bacterial infection that was followed by intense dizziness, fatigue and memory problems.

That was almost a decade ago, and since then she has struggled with the condition known as myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS. Ms. Caldwell, 56, of Hillsborough, N.C., said she could no longer ski, dance and work two jobs as a clinical research coordinator and caterer, but had to stay in bed most of the day.

“I haven't been right since, and I haven't worked a day since,” said Ms. Caldwell, whose symptoms include severe dizziness when her legs are not raised.

The condition has also left me “cognitively confused,” she said. “I can't read or understand something properly, I can't remember new things. It's 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 took part in a series of tests and evaluations of their blood, body and brain.

Findings from the studypublished Wednesday in the journal Nature Communications, showed remarkable physiological differences in the immune system, cardio-respiratory function, gut microbiome and brain activity of the ME/CFS patients compared to 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, in part because ME/CFS has long been dismissed or misdiagnosed. The findings confirm that “it's biological, not psychological,” said Dr. Avindra Nath, chief of nervous system infections at the National Institute of Neurological Disorders and Stroke, who led the study.

The findings could have implications for patients with a long Covid-19 epidemic, which often includes symptoms similar or identical to those of ME/CFS. Although the study participants were recruited before the pandemic, they all had a form of ME/CFS that is preceded by an infection, just as long as 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 patients in the study varied. (No one had Lyme disease; Mrs. Caldwell's infection was C. diff.)

The differences in the immune system were among the clearest findings, said Dr. Anthony Komaroff, a professor of medicine at Harvard Medical School, who was not involved in the study but served as a reviewer of the study for the journal. “They discovered chronic activation of the immune system, as if the immune system was engaged in a long war against a foreign microbe, a war that it could not completely win and therefore had to keep fighting,” he said.

Dr. Nath said his theory is that, in both long-term Covid-19 and post-infectious ME/CFS, “either bits and pieces of that pathogen are hanging around and driving this thing” or “the pathogen is gone, but whatever it has done is immune system, it just never settled down.”

Another striking finding was that when participants were asked to perform tasks measuring their grip strength, a part of their brain involved in coordinating and controlling actions showed reduced activation – while in healthy people it showed increased activation.

That area of ​​the brain, the right temporal-parietal junction, is involved in “telling the legs to move, telling the mouth to open and eat – it's kind of telling you to do something,” said Dr. . Komaroff. “If it doesn't light up properly, it's harder to get the body to make that effort,” he continued, adding that the NIH researchers “speculate that the chronic immune stimulation they found and the changes in the gut microbiome they found could lead to these brain changes, which then lead to symptoms.”

Experts warned 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 had 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 intensive evaluation during day-long visits to the NIH in Maryland.

“They selected fairly healthy patients,” says Dr. Carmen Scheibenbogen, 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, but it's just disappointing because it was such a invasive 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 seventeen patients “spontaneously recovered” from the condition, which she said is “not typical of ME/CFS.”

Both she and Dr. Scheibenboog also pointed out that the study did not find any medical signature of the condition that has been documented by other research. For example, patients were not found to perform worse on cognitive tests or to have neuroinflammation.

“These are well-established pathologies and are really critical to ME/CFS,” Ms Pollack said, adding: “So this hasn't addressed everything, and it contradicts some of the things we know.”

Dr. Scheibenboog said the key findings are that the condition is caused by dysregulation of the immune system, and that the researchers are clear that 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 viewed as just one step in understanding the condition, its severity and possible remedies. “We need to make progress toward research into treatments,” Ms. Pollack said.

For Ms. Caldwell, some aspects of the study participant experience were sobering, such as when she scored a 15 on a 100-point scale for physical functioning, and a 6.25 on a 100-point “vitality” scale measuring energy levels and measures 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 are on the cusp of being understood, so this study is a big deal,” she said. “I've been vilified, dismissed, invalidated and belittled for so long,” she added, “so the validation is huge for me.”