A Statement in Support of Cochrane

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