Cochrane has decided to temporarily withdraw a review of exercise therapies for the illness variously known as ME, CFS, ME/CFS and CFS/ME. The review reported that exercise therapy is effective in treating the illness, a finding that has provided unwarranted support for recommendations that patients should undergo the intervention known as graded exercise therapy. Yet Cochrane has found merit in complaints about serious scientific missteps and has asked the review team to respond accordingly.
Supporters of the approach to treatment endorsed by the Cochrane review have portrayed the decision for temporary withdrawal as a loss for science and an unfortunate capitulation to pressure from a vocal patient lobby. But patients have criticized the review not because they harbor anti-scientific views or are prejudiced against psychiatry. Rather, they have expressed reasonable and convincing concerns about the poor methodological choices made by the reviewers, who to date have not offered robust explanations.
We therefore believe it is important to voice our support for Cochrane’s effort to seek clarity on the issues raised not only by patients but by many others as well, including scientists, clinicians and academics. Here are some key reasons why we agree with Cochrane€™s decision:
1) The PACE trial, the largest of the eight studies included in the Cochrane review, has been internationally discredited because of its 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 contra-indicated and could cause harm.
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.
Vincent R. Racaniello, PhD
Professor of Microbiology and Immunology
Columbia University
New York, New York, USA
Host of Virology Blog
Christopher Armstrong, PhD
Bio21 Molecular Science & Biotechnology Institute
Department of Biochemistry and Molecular Biology
University of Melbourne
Melbourne, Victoria, Australia
James N. Baraniuk, MD
Professor of Medicine
Georgetown University
Washington, DC, USA
Lucinda Bateman, MD
Medical Director
Bateman Horne Center
Salt Lake City, Utah, USA
Jonas Bergquist, MD, PhD
Professor of Analytical Chemistry and Neurochemistry
Biomedical Centre
Uppsala University
Uppsala, Sweden
Charlotte Blease, PhD
Fulbright and Marie Curie Research Fellow
General Medicine and Primary Care
Beth Israel Deaconess Medical Center
Harvard Medical School
Boston, Massachusetts, USA
School of Psychology
University College Dublin
Dublin, Ireland
Bela Chheda, MD
Center for Complex Diseases
Mountain View, California, USA
Member, The ME/CFS Collaborative Research Center at Stanford
Palo Alto, California, USA
Joan Crawford CEng, MSc MA
Counselling Psychologist €“ Chronic Pain Management Service, NHS, UK
Private psychology practice €“ Chester UK.
Chair €“ Chester ME self help group (MESH), UK
Todd E. Davenport, PT, DPT, MPH, OCS
Professor & Program Director
Thomas J. Long School of Pharmacy & Health Sciences
Department of Physical Therapy
University of the Pacific
Stockton, California, USA
Ronald W. Davis, PhD
Professor of Biochemistry and Genetics
Stanford University
Stanford, California, USA
Kenneth J. Friedman, PhD
Associate Professor of Physiology and Pharmacology (retired)
New Jersey Medical School
University of Medicine and Dentistry of New Jersey
Newark, New Jersey, USA
Robert F. Garry, PhD
Professor of Microbiology and Immunology
Tulane University School of Medicine
New Orleans, Louisiana, USA
Rebecca Goldin, PhD
Professor of Mathematics
George Mason University
Fairfax, Virginia, USA
Alan Gurwitt, MD
Clinician in Private Practice (retired)
Associate Clinical Professor
Yale Child Study Center (retired)
New Haven, Connecticut, USA
Associate Clinical Professor
University of Connecticut Dept of Psychiatry (retired)
Storrs, Connecticut, USA
Lecturer, Harvard Medical School (retired)
Boston, Massachusetts, USA
Paul M. Guyre, PhD
Professor of Microbiology and Immunology
Geisel School of Medicine at Dartmouth
Hanover, New Hampshire, USA
Maureen Hanson, PhD
Liberty Hyde Bailey Professor
Department of Molecular Biology and Genetics
Cornell University
Ithaca, New York, USA
H. Craig Heller, PhD
Professor of Biology
Stanford University
Stanford, California, USA
Brian M. Hughes, PhD, FPsSI
Professor of Psychology
National University of Ireland Galway
Galway, Ireland
David L. Kaufman, MD
Center for Complex Diseases
Mountain View, California, USA
Member, The ME/CFS Collaborative Research Center at Stanford
Palo Alto, California, USA
Betsy Keller, PhD, FACSM
Professor of Exercise & Sport Sciences
Ithaca College
Ithaca, New York, USA
Eliana Mattos Lacerda
Assistant Professor of Epidemiology
Clinical Research Department
Faculty of Infectious and Tropical Diseases
London School of Hygiene and Tropical Medicine
London, England, UK
Bruce Levin, PhD
Professor of Biostatistics
Columbia University
New York, New York, USA
Susan Levine, MD
Clinician in Private Practice
New York, New York
Visiting Fellow
Cornell University
Ithaca, New York, USA
Alan R. Light, PhD
Professor of Anesthesiology
Professor of Neurobiology and Anatomy
University of Utah
Salt Lake City, Utah, USA
Ami Mac, MD
Director of Translational Medicine
Stanford Genome Technology Center
Palo Alto, Michigan, USA
David F. Marks, PhD
Editor
Journal of Health Psychology
& Health Psychology Open
London, England, UK
Marlon Maus, MD, DrPH, FACS
DrPH Program Director
School of Public Health
University of California, Berkeley
Berkeley, California, USA
Neil R McGregor, BDS, MDSc, PhD
Clinical Associate Professor
Faculty of Medicine, Dentistry and Health Sciences
Bio21 Molecular Science & Biotechnology Institute
University of Melbourne.
Melbourne, Victoria, Australia
Patrick E. McKnight, PhD
Associate Professor of Psychology
George Mason University
Fairfax, Virginia, USA
Jose G. Montoya, MD, FACP, FIDSA
Professor of Medicine
Division of Infectious Diseases and Geographic Medicine
Stanford University School of Medicine
Stanford, California, USA
Director, Palo Alto Medical Foundation Toxoplasma Serology Laboratory
National Reference Center for the Study and Diagnosis of Toxoplasmosis
Palo Alto, California, USA
Elisa Oltra, PhD
Professor of Molecular and Cellular Biology
Catholic University of Valencia School of Medicine
Valencia, Spain
Roshini C. Pinto-Powell, MD, FACP
Associate Professor of Medicine and Medical Education
Associate Dean of Students and Admissions
Co-director of On Doctoring
Co-director of Geriatrics and Ambulatory Medicine
Geisel School of Medicine at Dartmouth
Hanover, New Hampshire, USA
Deborah Rose, MD
Emeritus Adjunct Assistant Clinical Professor of Psychiatry
Stanford University School of Medicine
Stanford, California, USA
Peter C. Rowe, MD
Professor of Pediatrics
Johns Hopkins University School of Medicine
Baltimore, Maryland, USA
Donald R. Staines, MBBS, MPH, FAFPHM, FAFOEM
Clinical Professor
Menzies Health Institute Queensland
Co-Director, National Centre for Neuroimmunology and Emerging Diseases
Griffith University
Gold Coast, Queensland, Australia
Philip B. Stark, PhD
Professor of Statistics
University of California, Berkeley
Berkeley, California, USA
Leonie Sugarman, PhD
Emeritus Associate Professor of Applied Psychology
University of Cumbria
Carlisle, England, UK
Ronald G. Tompkins, MD, ScD
Sumner M Redstone Professor of Surgery
Harvard Medical School
Boston, Massachusetts, USA
David Tuller, DrPH
Senior Fellow in Public Health and Journalism
Center for Global Public Health
School of Public Health
University of California, Berkeley
Berkeley, California, USA
Mark VanNess, PhD
Professor of Health, Exercise & Sports Sciences
University of the Pacific
Stockton, California, USA
Workwell Foundation
Ripon, California, USA
Wenzhong Xiao, PhD
Assistant Professor of Bioinformatics
Harvard Medical School
Boston, Massachusetts, USA
Carolyn Wilshire, PhD
Senior Lecturer
School of Psychology
Victoria University of Wellington
Wellington, New Zealand
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