A draft document issued by the National Institutes of Health (NIH) in advance of an upcoming workshop on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has provoked strong opposition from the patient advocate community and some experts, who say the systematic literature review does not reflect the reality of the illness.
The draft document, "Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)," was commissioned by the Agency for Healthcare Research and Quality to inform a panel that will convene December 9 and 10 as part of the NIH Office of Disease Prevention's Pathways to Prevention ("P2P") series of workshops. The document is open for comments through October 20.
The P2P program's goals are to "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." Previous P2P topics have included polycystic ovary syndrome and opioids/chronic pain.
In addition, according to the P2P website, "P2P workshops are designed for topics that have incomplete or underdeveloped research [and] difficulty producing a report synthesizing published literature, and are generally not controversial."
In the case of ME/CFS, whose very name is the subject of debate, the literature is not only incomplete and underdeveloped but, patient advocates and some experts say, is also flawed by the use of multiple case definitions in studies, resulting in heterogeneous patient populations. This, they believe, has led to erroneous study results, notably in the controversial 2011 PACE (Pacing, graded Activity, and Cognitive behavior therapy: a randomized Evaluation) trial, which concluded that graded exercise treatment (GET) and cognitive and behavioral therapy are effective treatments.
The P2P draft document is based on a review of 28 observational studies on diagnosis and 36 intervention trials, including PACE. The draft concludes that "[cognitive and behavioral therapy] and GET have shown some benefit whereas other interventions have insufficient evidence to guide clinical practice." however, it includes a statement that "GET appears to be associated with harms in some patients."
Some ME/CFS experts do recommend very gentle exercise if the patient is able to do it to prevent deconditioning and may suggest counseling to help patients cope with the illness, but not with the expectation that either modality will improve the illness itself. (Patients often reject counseling because of the implication that their illness is psychological.)
"It's hard to identify research needs if you haven't articulated the current situation. I don't think they have done that," Kenneth J. Friedman, PhD, told Medscape Medical News. Dr Freidman is a coauthor of the International Association for CFS/ME's 2012 "ME/CFS: A Primer for Clinical Practitioners" and a former associate professor of pharmacology and physiology, New Jersey Medical School in Newark.
Dr Friedman and others also question whether ME/CFS should even have been included in the P2P process, which involves a "jury model," in which a panel of nonexperts will hear expert "testimony" during the December workshop and will produce another draft document immediately thereafter.
"When this [P2P] announcement came out, I said it's a fool's mission. It is so not appropriate for ME/CFS on so many levels," Dr Friedman said.
Jennie Spotila, a former litigation attorney who developed ME/CFS in 1994 and now serves as a patient advocate and blogger, strongly opposes the NIH's approach. "I'm not saying the P2P process is wrong for all conditions, but in this case we have some very serious concerns.... The P2P process is generally used in noncontroversial topics, and we're the opposite," she told Medscape Medical News.
In a statement to Medscape Medical News, David M. Murray, PhD, director of the Office of Disease Prevention, and Mariela Shirley, PhD, associate director for special projects and centers, Office of Research on Women's Health, NIH, Bethesda, Maryland, said, "Topics proposed for P2P workshops are generally not controversial in nature. However, the Office does not avoid controversial topics.... At multiple times during planning, experts (government officials, content-area experts, researchers, clinicians, and patient advocates) are consulted to determine if the P2P process and timing is the right fit."
Dr Murray and Dr Shirley also said the workshop panel will consider information from numerous sources in addition to the systematic literature review and that the review process is "guided by a Technical Expert Panel and the public has an opportunity to comment multiple times during the drafting of their final report."
Case Definition Conundrum
According to the P2P draft, "Uncertainty persists regarding the etiology and whether the condition reflects a single pathologically discrete syndrome, subsets of the same illness, or a nonspecific condition shared by other disease entities. Some suggest that an inciting event triggers an immune response and promotes immune and/or neuroendocrine dysregulation that perpetuates the body’s response and symptom experience that becomes ME/CFS. Viral etiologies have been predominantly studied based on the observation that the majority of patients report a sudden onset of symptoms associated with a preceding febrile illness and enlarged lymph nodes. However, no specific virus or other infectious agent has been identified, and not all patients experience a preceding febrile illness."
The document says there are currently eight published symptom-based case definitions that have evolved since the first one was published by the Centers for Disease Control in 1988. That article's authors also coined "chronic fatigue syndrome," a name reviled by patients, who say it trivializes their condition.
The term myalgic encephalomyelitis is used in parts of Europe and Canada and is generally preferred by patient advocates. The US Department of Health and Human Services now officially uses "ME/CFS," although part of the debate surrounds whether the two terms should be considered synonymous or whether some of the case definitions define "CFS" and others "ME."
The CDC's 1994 revision, dubbed the "Fukuda Criteria," is still the most commonly used definition in the United States. It requires the presence of "profound fatigue" for at least 6 months with other medical or psychiatric conditions excluded and also requires the presence of four or more of a list of eight symptoms. That list includes three symptoms that experts consider to be "core" to the condition (postexertional malaise [PEM] after even mild physical or mental exertion, impaired memory or concentration, and nonrefreshing sleep) but does not require those symptoms to make the diagnosis.
"Fukuda is by far the most popular criteria, but PEM isn't mandatory. That's one of the criticisms of it," Dr Friedman said.
Many experts in the field instead endorse the 2003 Canadian Consensus Criteria, which require symptoms that interfere with activity for at least 6 months for adults and 3 months for children, including persistent or recurrent physical or mental fatigue, PEM, sleep dysfunction, pain, neurological/cognitive manifestations, and the exclusion of other medical or psychiatric conditions.
The Canadian criteria also require at least one symptom from two of the following three categories: autonomic symptoms, such as orthostatic intolerance and irritable bowel syndrome; neuroendocrine abnormalities, such as cold or heat intolerance; and immunologic symptoms, such as tender lymph nodes or recurrent influenza-like symptoms.
In contrast, the Oxford Criteria, used in the United Kingdom and in the PACE trial, only require "severe disabling fatigue" with symptom duration of 6 months or longer, affecting both physical and mental functions and present 50% or more of the time, with other medical or psychiatric diagnoses excluded. None of the "core" symptoms are mentioned.
As the P2P draft document itself notes, regarding the varying case definitions, "those that require the symptoms of PEM and neurological and autonomic manifestations appear to represent a smaller but more impaired subset of the broader population."
Dr Murray and Dr Shirley told Medscape Medical News, "Multiple case definitions for ME/CFS have been developed to meet clinical and research needs. NIH encourages researchers to use the case definition that best meets their needs for rigorous scientific exploration of the cause(s), underlying pathology, potential therapeutic targets, and prevention of ME/CFS."
However, many in the ME/CFS community believe that agreement on defining the illness (or illnesses) will be necessary to move the field forward.
Leonard A. Jason, PhD, professor of psychology and director of the Center for Community Research at DePaul University, Chicago, Illinois, told Medscape Medical News that the use of multiple case definitions is one of the main challenges in the field and has hampered the ability of researchers to identify a homogenous group of patients from whom biomarkers can be identified as potential diagnostic tests and in whom potential therapies can be tested.
Dr Jason, who was also a coauthor of the 2012 International Association for CFS/ME primer and has conducted extensive research on various aspects of ME/CFS, including the case definition question, declined to comment on the P2P draft because he is among the experts scheduled to speak at the December workshop.
However, he did tell Medscape Medical News, "There's nothing more important in our entire field than getting this case definition right. Without a good case definition that's used by different researchers, we're going to constantly have some of the problems that have been reported with heterogeneous samples. We've got to get samples that really have the illness and don't have something else."
In fact, another federal government–commissioned project is aiming to do just that, at least for clinical use. An Institute of Medicine ad hoc committee composed of both ME/CFS experts and nonexperts was convened in September 2013 and charged with recommending clinical diagnostic criteria. The report from that effort, which is also not without controversy, is due out in early 2015.
Dr Murray and Dr Shirley told Medscape Medical News that although the goals and expected outcomes of the Institute of Medicine (IOM) and P2P efforts differ, "overall, the recommendations from the reports from the IOM and P2P will provide essential information for understanding the clinical case definition (IOM) and research possibilities (P2P) for ME/CFS that will move the field forward with better tools and enhanced methods to address this public health need."
Other Literature Limitations
In addition to the heterogeneity problem, Dr Friedman also pointed out that the P2P review included only studies published in indexed journals, whereas the majority of the literature on ME/CFS has been published in two nonindexed journals: the Journal of Chronic Fatigue, a quarterly published from 1995 to 2007, and Fatigue: Biomedicine, Health & Behavior , a quarterly just launched in 2013 by the International Association for CFS/ME.
"Why stick to the indexed literature for an illness when a good proportion isn't indexed? At best, they're doing a biased sampling of what's out there," Dr Friedman told Medscape Medical News.
Another concern, he said, is that many of the studies that did end up in indexed journals are in the psychological literature, reflecting the widespread belief that the condition is partially or wholly psychosomatic. "In my opinion, there is an overabundance of psychological literature that has been published on a very select population."
Even the more scientifically conducted studies suffer from another problem: The most severely affected patients are unlikely to participate in studies.
"All the studies that have been published have been published on an ambulatory CFS population. The extent to which the ambulatory population represents the spectrum of CFS patients is really not known. I don't think there is a rigorous study that informs how many ambulatory vs housebound vs bedbound patients there are in any given geographical area," Dr Friedman said.
"If you're lying in bed and you can't move your head and you have to speak in whispers, graded exercise therapy is not going to help you, and were you to attempt it, it would most likely kill you," he told Medscape Medical News.
"There's No Money"
Patient advocates and experts point to the lack of funding from the NIH itself as the real problem underlying the inadequate literature base. For the past several years, NIH funding for ME/CFS has hovered around $5 to $6 million, which is approximately 600-fold less than HIV/AIDS receives, despite roughly the same number of people, about 1 million, in the United States who have each condition.
Much of the ME/CFS research currently taking place, even at prestigious academic institutions such as Stanford University in California and Columbia University in New York City, is privately funded, with at least one recent attempt at crowdfunding.
"Nowhere in the discussion of limitations of the evidence base do they say anything about the impact of funding on the science," Spotila said, noting that the review excluded a large number of studies deemed to lack sufficient quality — the only studies investigators could afford to conduct.
"They excluded studies because they're low quality, but that's the stuff that's cheap to do. So our studies are small, they are case-control, they don't have all of the statistical power you would expect, because there's no money…. It's a major, major problem in this field. It has a huge impact on our evidence base."
Dr Friedman and Dr Jason agree. "If we had adequate funding, certainly we'd have the larger samples that the P2P is asking for," Dr Jason told Medscape Medical News.
Dr Friedman said, "The government should be embarrassed that the private sector has had to take over because of their lack of funding."
Asked to comment on that, Dr Shirley told Medscape Medical News, "The amount of funding spent on a specific area of research is driven by the number of researchers in a specific research field, the experience of researchers in a scientific field to successfully compete for NIH funding, the number of submissions to NIH for funding, and the success of those submissions during NIH peer review. Taken together, all of these factors influence the likelihood of successful outcome for NIH funding in any scientific area, and thus the amount of funding to support meritorious research."
Dr Jason is hopeful this new attention from the federal government could lead to progress. "On the positive side, there is going to be more attention focused on this area than ever before, and that's good for everyone. This [P2P] provides an opportunity for lots of voices to get out, and for people to hopefully make some critical decisions that are important for the field.... Sometimes the best thing that can happen is to get focused attention and get people thinking seriously about this."
Dr Friedman, Dr Jason, Spotila, Dr Murray, and Dr Shirley have disclosed no relevant financial relationships.
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Cite this: Chronic Fatigue: NIH Literature Review Faulted - Medscape - Oct 17, 2014.