National Institutes of Health researchers who began what may be the deepest biological investigation ever of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are writing up their findings and plan to circulate a draft among their large team of scientists and physicians for feedback soon. 

“The study will help patients and should move the field forward in a big way,” said NIH neurovirologist Avindra Nath, the principal investigator of the study that brought ME/CFS patients into the agency’s large Clinical Center in Bethesda, Md. “The huge benefit is to move toward clinical trials” of drugs, he added. 

Nath said the study has identified consistent biological problems in ME/CFS patients, who spent up to four weeks as NIH inpatients over two visits. “It was important to convince ourselves that there really are biological problems that are reproducible and consistent, and to develop expertise to study ME/CFS, because we hadn’t looked at it before. Then we will move on to treatment studies. We have a number of different candidates [drugs] we would like to try.” 

The study was launched in late 2016 after then-NIH director, Francis Collins, responded to patient pressure to invest in helping patients with a long-neglected and often-devastating chronic illness. While the study protocol was approved quickly, completing the study has lagged. 

Representatives from #MEAction repeatedly pushed NIH to speed up the study before COVID. In a public letter and personal conversations with Nath and Walter Koroshetz, director of the NIH’s National Institute of Neurological Disorders and Stroke, #MEAction asked the NIH team to bring in two patients simultaneously and otherwise find ways to increase their pace. 

The research involved extensive substudies of immunology, physiology, metabolism, autonomic function, and more. Patients gave detailed histories of their illness, donated blood, spinal fluid, skin and muscle tissue, underwent magnetic resonance imaging scans, cognitive testing, sleep studies, cardio-pulmonary exercise tests, and spent several days in a metabolic chamber. More than thirty researchers from across NIH participated. 

Nath admitted that it has taken him too long to complete and write up the research. “COVID has pretty much taken over my life,” he said. In March 2020, the Clinical Center closed to most patients, ending enrollment a few patients short of the initial goal. Nath then began autopsy studies of people who died of COVID-19 and eventually began studying people with Long COVID, or as the NIH terms it, post-acute sequelae of COVID. Nath has said that many cases of Long COVID strongly resemble ME/CFS. 

With patient investigations ended at the start of the pandemic, Nath assembled five working groups to analyze the ME/CFS study’s huge data sets. “We had an immunology group, a physiology group, and so on,” he said. “The analyses are very cumbersome and take a long time. It’s all slower than anyone wants, including myself.” 

Last fall, Nath and the study’s lead clinical investigator, Brian Walitt, began meeting every weekend to synthesize the findings and to write up the results. Nath, who has an extensive track record of publishing research in top journals, and whose research is cited more than 45,000 times in the medical literature, said, “I’ve never written a paper of this huge magnitude in my life. I feel badly that it’s taken so long. But we have so much to synthesize, Brian and I. Today we were working on the discussion section,” which usually appears at the end of a research report and tries to put the results in a larger context.   

Nath acknowledged that patients want to see results, but when asked if he would consider posting the draft paper as a preprint – a method of sharing research before formal peer review – he balked. He said top medical journals tend to reject papers that have gotten attention as preprints, and he also favors letting peer review run its course before sharing findings.  

Nath also said that the NIH intramural research program – its scientists who work in Bethesda – has now developed expertise in studying and understanding ME/CFS and related conditions. The Veterans Administration has asked his team for help in studying veterans with Gulf War Syndrome using a similar in-depth protocol, and the intramural group is also continuing to study Long COVID patients who they say will meet ME/CFS criteria. We are reaching out to NIH to learn how they will be diagnosing ME/CFS in study participants and whether they will use the same strict protocol used for diagnosis in the ME/CFS intramural study.