In recent months, two developments have provided some degree of optimism to people with the illness variously called chronic fatigue syndrome, myalgic encephalomyelitis (“inflammation of the brain and central nervous system, with muscle pain”), CFS/ME, and ME/CFS — the term often used these days by U.S. agencies. Taken together, these developments herald the welcome possibility of significant changes in research and treatment policies for the illness, which is estimated to afflict between 1 and 2.5 million people in the U.S. They also reinforce a critical but often overlooked point: patients can possess far more wisdom about their condition than researchers and policymakers guided by their own biases and misperceptions.

New Research Effort

On October 27, Francis Collins, director of the National Institutes of Health (NIH), announced a major new initiative to unlock the disease’s physiological mysteries. The announcement marked a significant shift away from the agency’s history of downplaying the illness; it was also an implicit admission of that longstanding neglect. In recent years, the NIH has spent only about $5 million annually on research, far less than the amount allocated for conditions with fewer sufferers but more effective lobbies, more powerful congressional supporters, or greater public awareness and understanding.

Collins promised that more funding would be available. “It will be substantially greater than the current five or six million a year,” Collins told NPR of the upcoming research effort. “We are going to ramp this up.”

For decades, the U.S. government has mostly ignored the plight of patients with ME/CFS, with many in the medical community regarding it as a psychiatric condition. In the late 1990s, the Centers for Disease Control and Prevention (CDC) was found to have spent millions that Congress had earmarked for the illness on other priorities. Frustrated patients and advocacy groups have long clamored for more research dollars and government attention, to little avail. But the debate shifted sharply in 2015, paving the way for the recent NIH announcement.

Reports released in February and June of last year, from panels commissioned by the Institute of Medicine and the National Institutes of Health, both portrayed ME/CFS unequivocally as a devastating disease marked by major immunological and neurological dysfunctions, often apparently triggered by an infectious illness or some other exposure. The reports strongly recommended aggressive research strategies to crack the problem and find pharmaceutical treatments. Also last year, scientists from Columbia University identified distinctive immune system patterns among people with early stages of the illness, generating hope that research might lead to a diagnostic biomarker in the future.

Investigating The PACE Trial

The other significant development last fall was the emergence of a powerful public challenge to the largest clinical trial of ME/CFS: investigators had reported in a 2011 Lancet paper that exercise and a form of psychotherapy were effective treatments. On November 13, 2015 leading scientists from Columbia, Stanford, Berkeley, and elsewhere issued a strongly worded open letter to The Lancet and its editor, Richard Horton, demanding that the journal seek an independent review of the study, called the PACE trial. (The paper’s full title: “Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome: a randomised trial”)

The PACE results have exerted a major influence on public health policies, clinical treatment guidelines, and societal attitudes, not just in the U.K. but in the U.S. as well. Yet the open letter, posted on Virology Blog, a site hosted by Columbia microbiology professor Vincent Racaniello, stated that the trial’s many documented flaws “have no place in published research.” Lancet editor Horton has not responded to the open letter.

In full disclosure, the open letter was prompted by my own investigation of the PACE trial, which was posted on Racaniello’s blog from October 21-23. In the series and subsequent articles, I delved deeply into what I believe to be a slew of serious methodological missteps committed by the PACE investigators, a prominent group of British mental health professionals. My interest in the trial was sparked by conversations with patients and advocates who had analyzed its shortcomings and documented their findings in well-researched reports, journal correspondence, and blog posts.

In the Virology Blog series, the problems I examined included: mid-trial changes in the primary outcome measures and a significant relaxation of all four criteria for “recovery,” without any sensitivity analyses to assess the impact of the changes on the results; inclusion of outcome thresholds for improvement and “recovery” that demonstrated worse health than entry criteria for disability; publication of a newsletter for participants that promoted the therapies under investigation; rejection of the study’s own objective measures as irrelevant or inaccurate after the results proved disappointing; and failure to tell participants of investigators’ close ties to insurance companies, despite the trial protocol’s promise to disclose “any possible conflicts of interest” and “institutional affiliations” while obtaining informed consent.

In addition, the researchers used a very broad definition of the illness to identify patients, requiring only one symptom — six months of disabling, medically unexplained fatigue. (Many different definitions have been used for research and clinical care.) Last June’s report from the NIH panel noted that this definition, known as the Oxford criteria, identified people with a range of fatiguing conditions, not just those with ME/CFS. Because heterogeneous samples render it difficult if not impossible to interpret study results, the NIH panel suggested that the Oxford criteria could “impair progress and cause harm” and should therefore be “retired” from use.

More widely accepted definitions of the illness are more restrictive and identify the core symptom not as fatigue but as the body’s abnormal response to even minimal activity — a severe weakening known as “exertion intolerance” or “post-exertional malaise,” among other terms. While the PACE study used two alternate sets of criteria to conduct sub-group analyses drawn from the larger, Oxford-criteria sample, methodological problems make it difficult to interpret these sub-group results.

Besides the scientists’ open letter to The Lancet, the Virology Blog investigation triggered a wave of anger among patients; a petition calling for retraction of the main PACE findings quickly gathered more than 10,000 signatures. The investigation also sparked a letter from a dozen major ME/CFS advocacy groups to federal health agencies requesting them to revise materials and policies informed by PACE and other studies that used the broad Oxford criteria. Because such studies include participants without ME/CFS, the organizations noted in their letter, the findings should not be assumed to be appropriate for those who actually have the illness. (The responses from the agencies were polite but failed to resolve the concerns raised.) Psychologist James Coyne further ramped up the public pressure by seeking data from another PACE paper, a 2012 economic analysis published in PLoS One, basing his request on the open-data policies of PLoS journals. The investigators rejected the request as “vexatious.”

Challenging An Entrenched But Flawed Treatment Approach

What makes these public rebukes of PACE so noteworthy is that they take on a well-established treatment paradigm that has, for years, successfully defended itself against vigorous criticism from patients and advocacy groups. The critics note that the framework ignores the mounting scientific consensus that serious physiological dysfunctions cause the symptoms plaguing ME/CFS patients.

According to the PACE theory, the exhaustion, cognitive dysfunction, sleep disorders, muscle pain, and other characteristic traits of ME/CFS are not caused by an organic disease. The PACE investigators acknowledge that an initial viral infection or other illness can trigger the syndrome. But once that infection or illness passes, the theory holds, patients remain falsely convinced they are still sick, refuse to engage in activity as a result, and become severely deconditioned. Muscle atrophy and other debilitating physical effects of deconditioning, not an underlying pathology, are presumed to be the source of the many troubling symptoms.

Graded exercise therapy was designed to help patients get back into shape with incremental increases in exertion. The psychotherapy used in the trial was a specific form of cognitive behavior therapy. It was designed to help patients abandon what the PACE team viewed as their “unhelpful belief” that they suffered from a medical disease preventing them from being active. The researchers argued, in a 2013 paper in Psychological Medicine, that patients could achieve “recovery” with the two treatments.

In the U.K., the National Health Service has focused primarily on providing these two therapies and related rehabilitative treatments. The treatments are somewhat less common in the U.S., but the framework and ideas promoted by the PACE investigators have nevertheless strongly influenced public health officials and clinicians. Even when U.S. doctors do not know specifically about the PACE trial, they are likely to have heard from news reports or medical colleagues that psychotherapy and exercise have been shown to be effective.

That message has been disseminated through other means as well. Leading clinical guidelines for managing the illness, including from the CDC, the American Academy of Family Physicians, the Cleveland Clinic*, Kaiser Permanente, and UpToDate (a widely used online “decision support” resource for clinicians), recommend cognitive behavior therapy and graded exercise therapy as treatments. These guidelines cite PACE and related studies as supporting evidence. The PACE trial has also been included in influential meta-analyses, literatures reviews, and other publications directed at clinicians, health administrators, and others who interact with ME/CFS patients or make decisions about their care.

Until such references are removed, said patient advocate Mary Dimmock, the treatment of people diagnosed with the illness will continue to be influenced by research that includes those with other conditions. And that’s a problem because people with ME/CFS can suffer serious, long-term relapses if they push themselves to do more than their bodies can handle — meaning that increasing their exercise levels might not only be useless but even cause them to get worse.

“Basing recommendations for ME/CFS on studies like PACE that include patients who do not have ME/CFS is not only bad science but is medically unethical and creates a serious risk of harm,” said Dimmock, who became an advocate several years ago after her son fell ill. (Dimmock organized the letter from ME/CFS advocacy groups urging federal health agencies to revisit recommendations based on the PACE framework.)

In an email exchange, Elizabeth Unger, chief of the chronic viral diseases branch at the CDC, noted that recent developments—including the Institute of Medicine and NIH reports earlier this year, and the NIH announcement in October—“have moved the field beyond the PACE trial.” But she did not respond directly to questions about whether she felt the documented flaws of the PACE study, such as publication of participant testimonials and overlapping thresholds for disability and “recovery,” were acceptable research methodologies.

Unger acknowledged that the CDC’s current webpage for the illness cites graded exercise therapy and cognitive behavior therapy as possible management tools, but she noted that the site contains “no mention of cure or false cognitions about illness” — two of the biggest criticisms of the PACE approach. Yet advocates like Mary Dimmock accurately note that the evidence base for using GET and CBT relies on the flawed PACE trial and some smaller studies, mostly conducted by the same group of researchers and their colleagues.

Looking Ahead

Although the recent developments offer some room for hope, patients and advocacy groups are tempering their expectations. The high-profile battle over PACE has certainly galvanized patients in the U.S., the U.K., and elsewhere and has attracted the attention of a growing number of critics from outside the ME/CFS community. Advocates remain concerned, however, that the spirited public debate has not yet impacted clinical and treatment guidelines that include recommendations based on PACE and related studies.

And although the announcement of the NIH initiative generated headlines, the effort is still in the planning stages. Collins appears committed to seeking significant patient involvement — an essential step in reversing course. But there have been no funding commitments, and no decision has been made on which definition of ME/CFS will be adopted to ensure that studies include only those with the disease. As a result, many are skeptical that anything will really change. If it does, the reason will likely be because public health and medical authorities have finally done what they’re supposed to: listen to patients and trust them as experts on their own illness.

* Correction November 1, 2016: An earlier version of this article incorrectly stated that the Cleveland Clinic was among the institutions that still included cognitive behavioral therapy and graded exercise as recommend treatment for ME/CFS. In fact, Cleveland Clinic let that recommendation expire in 2014 and has not replaced.