Long before the world had heard of long COVID, Sanna Stella experienced firsthand how a simple respiratory infection can shape-shift into a chronic illness.
In 2014, a case of bronchitis left Stella, a therapist who lives in the Chicago area, with debilitating fatigue.
Within a month, she was barely able to walk from the couch to her kitchen table. Eventually, Stella learned she had chronic fatigue syndrome, now called myalgic encephalomyelitis/chronic fatigue syndrome, or simply ME/CFS.
Patients can suffer from a range of symptoms, including profound exhaustion, brain fog and post-exertional malaise, an escalation in symptoms following exertion. There is no FDA-approved treatment for the illness, which affects more than 4 million people in the U.S.
Receiving an official diagnosis did little to change Stella's daily reality. "I got pretty frustrated and angry that I was going to be stuck in bed and nobody could do anything," she says.
She resolved to pour her energy into advancing understanding of the illness. So when picked to participate in an ambitious study led by the National Institutes of Health, Stella was all in, despite the physical toll that she knew would come with it.
"The whole thing was pretty tough," she says. "After the first four or five days, I could only get to testing on a stretcher, but I just wanted to be able to contribute so that we could make progress."
After seven years, the research was finally published in Nature Communications this week. It gives an unusually exhaustive look at the biological abnormalities that can arise in ME/CFS, spanning the brain, the gut, the immune system and the autonomic nervous system.
A deep look at a long-neglected illness
The findings underscore that the symptoms cannot be explained by physical deconditioning or psychological factors, says senior author Dr. Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke.
"We can very emphatically say that we don't think that's the case," he says. "There are true biological differences."
The results largely corroborate what's already known by those in the field, but the data-rich snapshot of the illness stands out because of how deeply it probes the illness — and the possibility that it may bring new momentum toward testing potential treatments.
Dr. Nancy Klimas calls it the most thorough evaluation she's ever seen of any disease in a clinical study.
"It's an amazing study," says Klimas, who directs the Institute for Neuro-Immune Medicine at Nova Southeastern University in Florida. "This is the kind of data set that can actually lead to a clinical trial [for new treatments] and that's what our patients want the most."
Launched in 2016, the study was disrupted by the COVID pandemic, which slowed its progress and limited the number of participants — only 17 ME/CFS patients were ultimately included.
Still, the findings may actually get more attention than they might have otherwise because of the overlapping symptoms in ME/CFS and long COVID.
The precise underlying cause of ME/CFS isn't known, although there are a number of theories. Many cases, but not all, seem to develop in the aftermath of an acute infection, for example with the Epstein-Barr virus or other bugs.
Research languished for decades while it was denigrated as "purely psychological," and to this day, few clinical trials are underway, says Maureen Hanson, a professor of molecular biology and genetics at Cornell University.
Better understanding of an immune system "at war"
The NIH Intramural study involved more than 75 scientists and cost millions of dollars to complete.
The participants were painstakingly selected from a pool of more than 200 patients to ensure they had the correct diagnosis and that it could be traced back to an infection. There were also detailed psychological and medical evaluations.
Those enrolled spent several weeks at the NIH Clinical Center in Bethesda, Md., and underwent a battery of tests — everything from muscle biopsies to hours spent in tightly controlled metabolic chambers.
The authors conclude that ME/CFS is primarily a brain disorder, probably brought on by immune dysfunction and changes in the gut microbiome.
Dr. Anthony Komaroff, who studies ME/CFS at Harvard Medical School, says this is fully consistent with existing research.
The study provides compelling evidence, he says, that the immune system is chronically activated: "As if it's engaged in a long war against a foreign microbe, a war it couldn't completely win and therefore had to continue fighting."
Nath and his co-authors say their findings suggest that something leftover from an infection — an antigen — continues to perturb the immune system. This "chronic antigenic stimulation" triggers a cascade of physiological events that eventually manifest as symptoms.
It's a theory that builds on work done by researchers like Hanson, who has found evidence of dysfunction, or "exhaustion," in T cells, which can happen when these immune cells are continuously exposed to the same antigen.
"When they become exhausted, they are less able to do their job, which is to fight against pathogens," says Hanson. "So it's an important consequence of having a chronic infection."
While this theory has gained traction, both for ME/CFS and long COVID, she says there are other possibilities. It could be that an infection triggers an autoimmune response or in some other way sparks problems in the immune system.
"Maybe all three things are going on," she says.
Understanding the fatigue
The study also delves into how dysfunction in the brain and nervous system can help explain cognitive and physical symptoms, including exhaustion.
Many people with ME/CFS, says Klimas, "have learned that if they do too much, they will relapse."
Samples from spinal fluid reveal abnormally low levels of certain neurotransmitters like dopamine and other molecules that are involved in regulating the nervous system, and those deficits were linked to symptoms.
Researchers also looked at differences in brain activity during a physical task, in this case, a repeated test of grip strength.
A region of the brain that's involved in perceiving fatigue and generating effort was not as active in those with ME/CFS.
"Their brain is telling them, 'no, don't do it,'" says Nath. "It's not a voluntary phenomenon."
This is a novel observation, says Komaroff, demonstrating that a brain abnormality makes it harder for those with ME/CFS to exert themselves physically or mentally.
"It's like they're trying to swim against a current," he says.
Limits and future directions
Despite the huge amount of data collected, the small number of people in the study and its strict inclusion criteria mean the findings don't necessarily apply to the broader ME/CFS patient population.
To begin with, participants had to be well enough to travel and undergo a huge volume of tests.
"These patients aren't necessarily as sick as many ME/CFS patients," says Dr. Lucinda Bateman, medical director of the Bateman Horne Center in Utah, which treats patients with ME/CFS.
Bateman says the study was well executed and comprehensive, but she doesn't see anything groundbreaking. However, she's hopeful the data will serve as a "foundation" for future research.
There were also some notable gaps in what the study turned up. For example, there was no evidence of autoimmunity, which has been documented elsewhere.
Given the study's small size, Komaroff says it's hard to conclude that "what you didn't find in this study is really not there."
Bateman says she was disappointed the team did not shed more light on post-exertional malaise. That's the escalation of illness that develops in the days after patients push themselves.
"It's the thing that makes people not want to give effort," she says. "We know if you do the [cardiopulmonary exercise] test again the next day, they cannot equal their performance on that test with the same amount of effort physiologically."
Seeds of future trials of treatments
With the results of the long-awaited study now published, the question for many patients is — what's next?
The NIH team suggests a type of cancer drug, immune checkpoint inhibitors, as one option that could be studied for ME/CFS.
Nath points out that the NIH has already launched a clinical trial on human immunoglobulin (IVIG) for long COVID patients, which he says will also inform research on ME/CFS.
While these conditions share striking similarities, Hanson believes the two cannot be seen as entirely interchangeable.
"We need to be studying long COVID as a group and ME/CFS as a group and compare these two groups, but not just mix them together," she says.
She and Bateman are helping the federal government design a roadmap that will set research priorities for ME/CFS, an effort that she hopes will stir up more funding for clinical trials.
"It's really imperative to start doing clinical trials for people who've been sick for decades. Many people have lost most of their adult life to this illness," she says.
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