BETHESDA, Maryland — The National Institutes of Health (NIH) held a 2-day conference on high-level science that is beginning to yield clues to understanding and ultimately treating the complex, multisystem illness now known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
The Accelerating Research on ME/CFS Meeting, held on the NIH’s main campus on April 4 – 5, brought together experts in basic science, clinician researchers, patients, and patient advocates to share the many research approaches being taken. These include studies in genomics, metabolomics, metabolism, immunology, microbiome, and brain imaging. Many of these studies have identified biological perturbations in patients with ME/CFS that are distinct from normal persons or comparison control patients.
The day before the meeting, on April 3, the NIH sponsored a day-long meeting, Thinking the Future: A Workshop for Young/Early Career ME/CFS Investigators, aimed at bringing new researchers into the field. About 40 persons attended. Some presented posters of their work at the main meeting.
The NIH has tripled its research funding for ME/CFS in recent years, from just $5 million in 2014 to $16 million in 2018. Part of that money has gone to three collaborative centers — Columbia University, in New York City; Cornell University, in Ithaca, New York; and the Jackson Laboratory, in Farmington, Connecticut. At the conference, speakers from each of those institutions gave updates on their work.
On the NIH campus, an in-depth intramural study is investigating a narrowly defined group of about 20 patients who meet multiple criteria for ME/CFS. These patients developed the illness after experiencing a confirmed infection. They have been ill for a period of 6 months to 5 years. In the study, they are being compared to healthy control persons and to patients with confirmed Lyme disease. An interim analysis of data will be conducted soon.
In a brief address, Francis Collins, MD, PhD, director of the NIH, called the conference “a real milestone in our efforts to understand the cause and ultimately to find preventions and cures for ME/CFS” and told the audience that he is “deeply committed” to finding answers.
Collins said that research recommendations included in the landmark 2015 Institute of Medicine (now the Academy of Medicine) report on ME/CFS led the NIH to resurrect its trans-NIH ME/CFS working group, which includes scientists from nearly all of the 27 NIH institutes and centers. The working group is led by Walter Koroshetz, MD, a neurologist who directs the National Institute of Neurological Disorders and Stroke (NINDS), along with dedicated program officers.
That move, Collins said, allowed the NIH to ratchet up funding for the collaborative centers, launched in September 2017.
However, patient advocates say that the current funding level — which dipped slightly in 2019 — is not nearly enough to address the complexity of the illness, nor is it commensurate with the disease burden. It is estimated that in the United States, 1 to 2 million people have ME/CFS; of those, a quarter are homebound or bedbound, and from one third to two thirds are unemployed.
In fact, “ME/CFS is more underfunded vs burden than any disease in the NIH portfolio,” according to Arthur A. Mirin, PhD, a retired applied mathematician from California, whose 30-year-old daughter has been ill with ME/CFS half her life. Mirin spoke from the audience during a panel discussion held at the end of the conference. On the basis of disease burden, the NIH should be devoting slightly more than $200 million to ME/CFS, Mirin said.
That sentiment was echoed by one of the NIH-funded scientists, Maureen Hanson, PhD, of the center at Cornell University, who noted that although the available scientific tools to study the illness are far more advanced than they were when outbreaks of so-called chronic fatigue syndrome were first reported in the mid-1980’s, “like 30 years ago, what we don’t have is adequate funding. We still don’t have adequate respect for the seriousness of this illness.”
Koroshetz told Medscape Medical News that NIH funding is determined by the grant applications it receives. “Our big problem still is that the number of what we would consider NIH-level research going on in this space is still very small, so that means the money still is pretty small compared to the problem…. I’d love to see a doubling of applications in the next year, and a tripling after that.”
However, Hanson pointed out, “we have repeatedly heard that there aren’t enough researchers interested in studying this illness…. But the reason there aren’t more researchers is that the disease is extremely underfunded. This is a classic catch-22 that NIH can overcome only by investing more funds.”
Collins acknowledged the deficiency, noting that even the 2017 funding uptick is “not enough. I agree with you,” he said.
“There Is Something Biologically Terribly Wrong With These People”
Immunologist Derya Unutmaz, MD, who heads the NIH-funded Jackson Laboratory, has found immune system disturbances in deidentified cell samples from patients with ME/CFS, particularly in CD8 cells and T-helper 17 cells, which are involved in tissue inflammation.
While emphasizing that the precise relevance of the findings is not yet clear, Unutmaz told Medscape Medical News, “There are some really major perturbations…. When I look at the data, there’s something biologically terribly wrong with these people. I studied HIV for many years. This is the type of thing you would see in HIV-infected people.”
A graduate student of Hanson’s, Alex Maldonaro, presented data from their laboratory showing that in cytotoxic CD8 T cells from patients with ME/CFS, metabolism is diminished compared with healthy T cells when stimulated. She said they hope to investigate how that deficiency affects immune function, as well as other metabolic pathways to better understand the disease mechanism.
Long-time ME/CFS researcher W. Ian Lipkin, MD, of Columbia University, presented data from that center’s deep dive into bacteriomic, viromic, metabolomic, and epigenetic analyses. In examining the microbiology, for example, a notable finding was that in fecal samples from patients with ME/CFS, levels of bacteria that produce butyrate are reduced. Butyrate is important for controlling immune system function and apoptosis.
Other findings presented at the meeting included preliminary data from Jonas Bergquist, PhD, professor of pathology at Uppsala University, Sweden, demonstrating significantly elevated levels of neuroinflammatory biomarkers in cerebrospinal fluid of ME/CFS patients. In addition, whole-brain magnetic resonance spectroscopy data from Jarred W. Younger, PhD, of the University of Alabama at Birmingham, revealed metabolite and temperature abnormalities in several brain regions of ME/CFS patients.
Virologist Jose G. Montoya, MD, professor of medicine at Stanford University, California, presented the latest in his long-standing work on cytokine networks in ME/CFS and their associations with disease symptoms and severity. He has recently found correlations with HLA genetic susceptibility regions that are also linked to autoimmune conditions, including Hashimoto thyroiditis and primary biliary cirrhosis.
“ME/CFS is now an unfolding story of scientific discoveries that will result in targeted treatments for what appears to be a chronic, incapacitating inflammatory syndrome. The data from various groups are pointing in this direction,” Montoya said.
He noted that whereas patients with ME/CFS typically have many symptoms suggesting inflammation, such as flulike symptoms, arthralgias, and hypersensitivity, the traditional clinical measures of inflammation — sedimentation rate and C-reactive protein levels — are seldom elevated in those patients. “Unfortunately, lots of people in clinical medicine have used that argument, that these two tests are normal and therefore there’s no inflammation. That’s really a very short vision of the immune system.”
He elaborated to Medscape Medical News, “I believe our data probably open the door for the possibility that we can now use more targeted immunomodulators, specifically, cytokine-based interventions…. The exciting thing is, we now have an in-silico system where we can test these.”
Koroshetz told Medscape Medical News, “I think the message is that there is evidence coming out now for subsets with clear biological abnormalities that are being identified, and these are hopefully going to inform treatment decisions.”
“The Essence of Being a Doctor Is to Be Able to Take Care of the Patient as a Whole”
Koroshetz noted that ME/CFS is a challenging area of research for the NINDS “because of the stigma of the illness and the lack of commitment from the medical community…. We really need people to see this is a problem and attract researchers to follow these threads that are appearing from the research. Eventually, I think we’re going to figure this out.”
In the past, while working at Massachusetts General Hospital, Koroshetz cared for patients with ME/CFS and provided symptomatic treatment for orthostatic intolerance and other manifestations of neurologic illness. At the meeting, he urged clinicians who have been skeptical about the biological basis of ME/CFS to take another look.
“That skill set for taking care of the patient in front of them when there is a lot of mystery or ambiguity about what’s going on is going away…. We have our hammers and we’re looking for nails, but the essence of being a doctor is to be able to take care of the patient as a whole. That’s important for lots of people, especially those with conditions that cross many different areas…. [ME/CFS] is a serious health condition for lots of people, and it’s not getting even close to the adequate kind of clinical care it needs.”