Chronic Fatigue Syndrome Report: More Research Needed

Miriam E. Tucker

June 16, 2015

More research needs to be devoted to the condition known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), according to a position statement from an independent panel convened by the National Institutes of Health (NIH).

Among other requests, the statement calls for more bench-to-bedside research, better training and education of clinicians, identification of new funding sources, and improved treatment. It is one of four linked papers on ME/CFS published online June 16 in the Annals of Internal Medicine.

Two of the other papers are systematic reviews of the literature — one for diagnosis and one for treatment — both citing a dearth of good-quality evidence to inform clinical practice. Both reviews, which informed the position statement along with public comment, were funded by the Agency for Healthcare Research and Quality and conducted by a team from the Oregon Health & Science University and Providence Health and Services Oregon in Portland.

In the fourth paper, an editorial, Anthony L. Komaroff, MD, from Harvard University and Brigham and Women's Hospital in Boston, Massachusetts, notes that these new documents, along with the recent Institute of Medicine (IOM) report on ME/CFS, combine information from thousands of articles that demonstrate the biological underpinning of the illness.

Indeed, the position paper cites "strong evidence" that "immunologic and inflammatory pathologic conditions, neurotransmitter signalling disruption, microbiome perturbation, and metabolic or mitochondrial abnormalities" are "potentially important for the definition and treatment of ME/CFS."

Taken together, Dr Komaroff says, the NIH and IOM reports "should put the question of whether ME/CFS is a 'real' illness to rest. When skeptical physicians, many of whom are unaware of this literature, tell patients with ME/CFS that 'there is nothing wrong,' they not only commit a diagnostic error: They also compound the patients' suffering."

The Annals papers are the final product on ME/CFS from the NIH's "Pathways to Prevention" (P2P) program, designed "to host workshops that identify research gaps in a selected scientific area, identify methodological and scientific weaknesses in that scientific area, suggest research needs, and move the field forward through an unbiased, evidence-based assessment of a complex public health issue."

The workshop for ME/CFS was held December 9 and 10, 2014. Speakers included ME/CFS experts, and the five P2P panel members who authored the current position statement were, by design, scientists and clinicians who do not specialize in the condition.

Panel chair and lead author Carmen R. Green, MD, professor of anesthesiology and obstetrics/gynecology at the University of Michigan School of Medicine in Ann Arbor, told Medscape Medical News: "We've come out pretty strongly and said that this is a disease. We have said there needs to be more science.... I believe the NIH will use this document to think about what needs to be done in the field."

Asked to comment, ME/CFS expert Nancy Klimas, MD, director of the Institute for Neuroimmune Medicine at Nova Southeastern University in Miami, Florida, told Medscape Medical News, "This was the best effort so far by the NIH to bring a broad, thoughtful group of people to the table to discuss this problem, and they did it in a very well-informed way. It's good news for the field."

Dr Klimas, who spoke at the P2P workshop in December and served on the IOM panel, said she hopes the new P2P report will help increase NIH funding for research into the illness, which has thus far totaled just $5 to $6 million per year, in contrast to the estimated $2 to $7 billion cost of the illness cited in the position statement.

"It's a tremendously underfunded area.... My hope is that a report like this just doesn't end up being just a report, but that a significant action at the level of the director of NIH happens to solve the problem of funding larger-powered studies…the funding has been too small to power the studies adequately to make big and important statements."

Diagnostic Conundrum

The two literature reviews bear out Dr Klimas' statement about the limitations of the studies that have been conducted in this field.

For diagnostic criteria, the Oregon group reviewed 44 studies investigating nine sets of published clinical criteria defining ME and/or CFS, including the recent IOM definition, which requires postexertional malaise, elements of fatigue, sleep disturbance, and cognitive impairment or orthostatic hypotension to make the diagnosis.

The different case definitions tend to capture patients with different symptom sets that may not represent the same disease, lead author M. E. Beth Smith, DO, associate professor of medicine at Oregon Health & Science University, told Medscape Medical News.

"So, our recommendation was to use the same definition, or at least compare different definitions within the same cohort of patients to see where similarities and differences exist. I think the new IOM definition is really a promising step forward for research, and maybe will allow us to diagnose ME/CFS more consistently, but it really hasn't been studied at all," Dr Smith said.

She noted that the team found no studies that compared strategies for ruling out alternative diagnoses, or for specifically defining which other fatiguing conditions should be ruled out. In addition, of the 22 studies that looked specifically at diagnostic approaches, none were studied in situations of diagnostic uncertainty; that is, all were looking at people already diagnosed with the illness and comparing them with healthy controls.

"They could detect differences, but for distinguishing between this fatiguing illness and other fatiguing illnesses, there really haven't been studies for that.... You run into the problem of how to validate [a definition] when there's no gold standard."

In general, the group found that although none of the definitions have been adequately tested, those that define "ME" or "ME/CFS" identified patients with more impairment, lower functioning, and more severe symptoms than did those defining "CFS" alone.

Notably, the group found that the 1991 "Oxford Criteria" for CFS, which essentially require only 6 months or more of function-impairing severe unexplained fatigue, were the least restrictive, and therefore the most likely to include patients who would not meet the other criteria.

This is important because the Oxford definition has been used for inclusion of patients in treatment studies, including the highly controversial Pacing, Graded Activity and Cognitive Behaviour Therapy; A Randomized Evaluation (PACE) trial, that have found benefit for psychological interventions and graded exercise.

In recognition of that, Dr Green and colleagues write, "[C]ontinuing to use the Oxford definition may impair progress and cause harm. Therefore, for progress to occur, we recommend that this definition be retired; the ME/CFS community concur on a single case definition (even if it is not perfect); and patients, clinicians, and researchers agree on a definition for meaningful recovery."

(Dr Green told Medscape Medical News the IOM definition was not yet available at the time the panel wrote the position paper, but it could certainly be among the resources used to achieve the recommended goal.)

Insufficient Evidence for Treatments

In their evaluation of a total of 35 treatment studies, Dr Smith and colleagues found that none have been conducted in patients who strictly meet "ME" criteria. They recommend more definitive studies of patients meeting the various criteria, including ME, and adequate subgroup analyses, which they also found lacking in most of the studies.

"The counseling and behavior and exercise studies have been more broadly researched, and they have demonstrated broader benefit, but they've only been studied in patients meeting CFS case definitions.... I think that's the biggest limitation or gap in the current literature: They do show benefit in a broader population, but we don't know what the effect would be in the smaller population meeting ME or ME/CFS definition," Dr Smith said.

According to Dr Klimas, experts view those modalities as adjuncts to manage the consequences of the illness, not as primary therapies. She said that graded exercise can minimize deconditioning, but it must be undertaken with great care so as not to exceed the patient's aerobic threshold. "You will cause a relapse if you push them into their anaerobic zone," she cautioned.

The only other treatment identified in the review as having evidence for benefit is the investigational intravenous immune modulator and antiviral drug rintatolimod (Ampligen, Hemispherx), which the US Food and Drug Administration has repeatedly declined to approve because of insufficient data, but which Hemispherx continues to investigate in an open-label trial of patients with low natural killer cell activity, a company spokesperson told Medscape Medical News at the P2P meeting in December.

Going Forward

The position statement includes a long list of recommendations for research and training, including a biorepository of patient samples and the use of "genomic, epigenomic, proteomic, and metabolomic strategies to identify critical biomarkers that will be clinically applicable," as well as " 'omics'-based drug repurposing and neurobiology studies" and an overall investment in "bench to bedside research."

Organizationally, the panel advises that "[t]he NIH institutes and centers...and other U.S. Department of Health and Human Services agencies should coordinate research efforts to promote efficiency and effectiveness while using public–private partnerships to leverage existing NIH infrastructure and dollars."

Dr Green told Medscape Medical News that the panel recognized budgetary constraints. "Money can be reallocated or better targeted.... We think the NIH, as the premier research organization in the world, can be innovative and figure out a way to move this scientific field forward."

In a statement to Medscape Medical News, the NIH Office of Disease Prevention said although panel reports are not policy statements of the federal government, the NIH carefully considers the recommendations that are outlined in the final report. In addition, approximately 6 to 8 months after publication of a panel report, the NIH Office of Disease Prevention convenes a meeting of federal agencies to consider actions that might be taken to address the panel’s recommendations.

Dr Green and Dr Smith have disclosed no relevant financial relationships. Dr Klimas receives funding from Hemispherx for their clinical trial.

Ann Intern Med. Published online June 16, 2015.


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