Alison Sbrana was in the belly of an opera when her life changed. Down in the pit, surrounded by fellow orchestra members, she’d been straining to play her flute for half the show. As performers overhead enveloped the audience in arias, Sbrana felt like the Hulk was pulling on the tendons in the right side of her neck. “I begged anybody for meds at intermission,” she said.
Sbrana had contracted infectious mononucleosis, or mono, as college students do. The symptoms started during that early April performance of “Cinderella,” when Sbrana was a 20-year-old student on track for a flute career. And then the illness never went away.
A decade removed, she remembers how long it took to figure out she had myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS. It’s a disease that most often occurs after an infection. The body cannot clear the bug but keeps up its immune response to continue trying, making people with ME/CFS feel like they have a perpetual flu. It’s a fatigue that flattens, headaches and body pain and dizziness that worsen after exertion — physical activity, but also sometimes mental.
In 2022, 4.3 million American adults reported having ME/CFS, according to data from the National Center for Health Statistics. At least twice in history, new pockets of patients have emerged: once in the 1980s, and again since the Covid-19 pandemic began in 2020. But despite that burden of illness — and how thoroughly ME/CFS changes people’s lives — science doesn’t know enough about the condition. There is no treatment.
For decades, it was considered a women’s condition, and patients were told it was in their heads. Now research leaves no doubt: ME/CFS is a disease with clear biological hallmarks.
A new, detailed study from the National Institutes of Health takes the most rigorous look yet inside the bodies of patients with the condition. The 70-page manuscript, published in Nature Communications on Wednesday, took almost eight years and over $8 million to complete. It has more than 70 authors from 15 of the 27 NIH institutes.
For a disease that just decades ago was relegated to a dusty corner of science — and reduced to an issue women made up — the paper is a milestone, albeit one based on a small sample of patients. Using many different analyses, researchers confirmed that there are clear biological markers of illness. Namely, there’s a protracted immune response that exhausts T cells. No matter how much the body tries to fight whatever bug is in its system, it can’t win.
This inflammation is what makes people feel like they’re constantly battling a flu, researchers say. ME/CFS patients also had abnormal functioning in a part of their brain that governs effort. “When they are asked to exert themselves, it doesn’t light up as much,” said Anthony Komaroff, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital. “It’s like trying to swim against a current.”
Such changes in the brain make it so ME/CFS patients have a different tolerance for physical and mental exertion, and a different perception of fatigue. Every decision is made knowing that, if a sick person pushes their body too far, it takes them longer to recover. (It took Sbrana months to bounce back from her trip to the NIH Clinical Center because running all of the tests was so taxing on her body, she said.)
“That is not something that a person can wish on themselves or imagine that they have. It’s there. It’s real,” said Komaroff, who helped screen participants for ME/CFS but said he was otherwise not involved in the study. He has researched ME/CFS since the 1980s, when very little was known about these patients.
Other researchers in the field told STAT they also found some of the findings compelling, with the caveat that just 17 ME/CFS patients were included.
“This is really a tour de force,” said Mady Hornig, a physician-scientist who has studied ME/CFS and was not involved in the research. “There are clues that I think are really worthy of pursuit.”
Findings about the effect of ME/CFS on the autonomic nervous system, which controls involuntary processes, could be further probed to see what link it might have to the immune system, Hornig said. And more study is needed on connections to the gut microbiome, she said, which in its mysterious diversity helps shape the immune system and could factor into disease progression. (Hornig has long Covid and is a patient representative in the NIH’s RECOVER study, and she contributes to study manuscripts in that role.)
A major drawback of the ME/CFS study is its small sample size, experts told STAT. Everything must be confirmed in larger studies. The researchers had hoped to have at least 40 ME/CFS participants, senior author Avindra Nath said.
But the group of almost 500 people who inquired about participating as of December 2016 was narrowed down over time to 217 after phone interviews, and then to 27 who had a full medical review. A few dropped out, and some more were found to have previously unknown health conditions or diagnoses other than ME/CFS. In the end, just 17 patients flew to Bethesda, Md., and spent a week at the NIH’s Clinical Center undergoing testing. Twenty-five healthy volunteers were used as controls.
And then, right as recruitment and initial assessments were ending in February 2020, the pandemic began. The researchers had to stop the study. They decided to use the data they had already collected and offer as descriptive a study as possible, said Nath, clinical director of the National Institutes on Neurological Disorders and Stroke. “Most of the Covid time, we were sitting analyzing the data,” he said. “It was a massive undertaking.”
Because of the low headcount, some things could’ve been missed. Any similarities to people with long Covid, for example, will need to be studied separately. “We need to know at the molecular and biochemical level, how similar are pre-pandemic ME/CFS patients to people with long Covid? We don’t know that. There’s an assumption that they’re the same,” said Maureen Hanson, a professor and ME/CFS researcher at Cornell University who wasn’t involved in the study.
And certain suggestions in the paper come with a large grain of salt, including a theory that drugs used to help cancer patients’ bodies destroy tumor cells could also help people with ME/CFS finally beat their infections. The study didn’t point to any new therapeutic targets.
Most importantly, the work still doesn’t answer what is arguably the single most important question: What is causing ME/CFS, and how can it be treated? Researchers in the field think certain people may have a genetic predisposition that makes it more difficult for their body to clear an infection, so that could play a part. But if the disease can crop up after many different kinds of bugs, then what is the antigen — the molecule, protein, or thing — that’s driving an unrelenting immune response for months to years afterward? And why do some people get better, like the few study participants who had a spontaneous recovery, while many others don’t?
It’s hard to get specific on antigens because viruses and other infectious diseases are constantly circulating through the population. Just because someone has traces of one antigen in their system doesn’t mean it triggered ME/CFS. And antigens are also sneaky, sometimes tucking away into parts of the brain that aren’t easy to access. But until researchers can get closer to the truth, it will be difficult to actually help patients.
The researchers’ efforts and the NIH’s money would’ve been better directed at those mysteries, University of Minnesota neuroscientist Apostolos Georgopoulos said. “I think very little has been gained as far as the disease goes, and very little practical usefulness. Let’s say I am a patient, that I suffer from it … I mean, how better am I?”
Sbrana, the participant, said being in the study was a meaningful and empowering experience for her. But she was disappointed at how the pandemic delayed everything. When she was enrolled in the research, she’d been sick for four years. She’s approaching her 10-year anniversary in April. “I hoped that this study would be earth-shattering and groundbreaking,” considering how long it has been, she said.
Nath defended the study as a great effort and said it’s unrealistic to expect a single study to solve all of a field’s problems. But everyone STAT spoke to agreed that real answers — and treatments — are long overdue for ME/CFS patients, some of whom have been sick for decades.
“It shouldn’t have taken this long for this paper to publish, but that’s water under the bridge at this point,” Sbrana said. “Now, things need to be accelerated …because we have millions of new people living with this disease.”
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