It appears that Cochrane will NOT temporarily remove a review from its database that claims exercise therapy is effective for chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME), as a report in Reuters had indicated last week. Instead, Cochrane editors have added an editor’s note (that is all but invisible unless you really go searching for it) stating that the authors plan to respond to questions concerning the methodology of the review and the studies it surveys.
For the general audience not familiar with Cochrane, it is an important database of medical reviews and meta-analyses that medical providers around the world reference daily for information on diagnosing and treating disease. The review in question, Exercise Therapy for Chronic Fatigue Syndrome, surveys eight studies that look at the effects of exercise in ME and CFS, the largest being the PACE trial.
Cochrane editors had previously said that they would temporarily remove the review until the review’s authors could respond to the substantive questions regarding the methodology of the review and its studies, posed by researchers, scientists, clinicians and patients.
Instead, the Cochrane editors have added a note stating that “this review is subject to an ongoing process of review and revision following the submission of a formal complaint to the Editor in Chief… A decision on the status of this review will be made once this resubmission has been through editorial process, which we anticipate will be towards the end of November 2018.”
Last week, 40 academics and clinicians, including many prominent ME specialists, had signed a letter in support of Cochrane’s decision to temporarily pull the review until the authors respond to the comments.
“The reviewers need to provide substantive and satisfactory answers to Cochrane’s legitimate methodological and scientific questions. If they are unable or unwilling to do so, the review should be permanently withdrawn,” states the letter.
A re-analysis of the Cochrane review was also published this month that concludes that graded exercise therapy is unsafe and ineffective for ME and CFS. The re-analysis, by Mark Vink and Alexandra Vink-Niese, argues that the review should have drawn its conclusion from the objective outcome measurements used in the studies – i.e. measurements that objectively show how patients responded to the treatments, such as how many days they were able to work. Instead, the review relied on subjective self-reporting, where the patient is asked to report how they feel, which is an unreliable measure. 
“The analysis of the objective [editor emphasis] outcomes in the trials provides sufficient evidence to conclude that graded exercise therapy is an ineffective treatment for myalgic encephalomyelitis/chronic fatigue syndrome,” states the re-analysis.
The re-analysis points to other major problems with the studies, including its use of flawed diagnostic criteria for enrolling patients (the studies relied on the Oxford and Fukuda criteria), meaning the studies may have included participants who did not have ME or CFS.
Similarly, the letter issued by 40 academics and clinicians this week outlines the following five critiques of the review and exercise studies:
1) The PACE trial, the largest of the eight studies included in the Cochrane review, has been internationally discredited because of outcome-switching and many other flaws. Yet the review rated the trial as being at “low risk” of reporting bias. In a recent open letter to The Lancet, more than 100 experts, including many of us, expressed concern about PACE’s “unacceptable methodological lapses.”
2) Like PACE, the other studies in the Cochrane review are open label trials relying on subjective outcomes. Trials with this design are fraught with bias, which is why they are no longer considered as reliable evidence for making decisions and developing recommendations for biomedical treatment. The review ignored objective outcomes from exercise interventions, which have generally failed to confirm subjective reports of benefits.
3) Five of the studies included in the Cochrane review used the Oxford criteria, a case definition that only requires six months of unexplained fatigue to render a diagnosis. This case definition generates heterogeneous samples that likely include many people suffering from undiagnosed depression, anxiety disorders and other fatiguing conditions rather than the devastating illness in question. When the US Agency for Healthcare Research and Quality removed Oxford criteria studies from its own analysis, the agency found no evidence to support recommendations for graded exercise therapy. This re-analysis also reported more harms among those assigned to such treatment than among those in the comparison groups.
4) Six of the studies included in the Cochrane review tested graded exercise therapy as a treatment for the illness. This intervention has been predicated on the theory that the ongoing symptoms are not caused by underlying pathophysiological processes but by a fear of activity, which in turn leads to sedentary behavior and severe deconditioning. Yet there is no legitimate scientific evidence to support this theory. A 2015 report from the US Institute of Medicine (now the National Academy of Medicine) concluded that ME/CFS is not driven by psychological factors; biomedical research from major medical centers in the US, UK, Australia and elsewhere supports that conclusion.
5) Given the many methodological and scientific problems with the Cochrane review, its conclusion that exercise therapy is effective cannot be taken at face value. This is of particular concern because it is widely accepted that the cardinal symptom of the illness is post-exertional malaise, or what the Institute of Medicine report called “exertion intolerance.” In other words, patients can suffer prolonged relapses even after engaging in minor physical activities, suggesting that graded exercise therapy is contraindicated and could cause harm.