Evidence Synthesis Program Gulf War Illness: A Systematic Review of Therapeutic Interventions and Management Strategies April 2020 Prepared for: Authors: Department of Veterans Affairs Principal Investigator: Veterans Health Administration Michele Freeman, MPH Health Services Research & Development Service Shannon M. Nugent, PhD Washington, DC 20420 Co-Investigators: Prepared by: Chelsea K. Ayers, MPH Kara A. Winchell, MA Evidence Synthesis Program (ESP) Center Ashlyn Press, MPH Portland VA Medical Center Maya E. O’Neil, PhD Portland, OR Devan Kansagara, MD, MCR Devan Kansagara, MD, MCR, Director GWI Interventions Evidence Synthesis Program PREFACE The VA Evidence Synthesis Program (ESP) was established in 2007 to provide timely and accurate syntheses of targeted health care topics of importance to clinicians, managers, and policymakers as they work to improve the health and health care of Veterans. These reports help: • Develop clinical policies informed by evidence; • Implement effective services to improve patient outcomes and to support VA clinical practice guidelines and performance measures; and • Set the direction for future research to address gaps in clinical knowledge. The program is comprised of 4 ESP Centers across the US and a Coordinating Center located in Portland, Oregon. Center Directors are VA clinicians and recognized leaders in the field of evidence synthesis with close ties to the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center Program and Cochrane Collaboration. The Coordinating Center was created to manage program operations, ensure methodological consistency and quality of products, and interface with stakeholders. To ensure responsiveness to the needs of decision-makers, the program is governed by a Steering Committee comprised of health system leadership and researchers. The program solicits nominations for review topics several times a year via the program website. Comments on this evidence report are welcome and can be sent to Nicole Floyd, Deputy Director, ESP Coordinating Center at [email protected]. Recommended citation: Freeman M, Nugent SM, Ayers CK, Winchell KA, Press A, O’Neil ME, Kansagara D. Gulf War Illness – A Systematic Review of Therapeutic Interventions and Management Strategies. Washington, DC: Evidence Synthesis Program, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs. VA ESP Project #05-225; 2020. Available at: https://www.hsrd.research.va.gov/publications/esp/reports.cfm. This report is based on research conducted by the Evidence Synthesis Program (ESP) Center located at the located at the Portland VA Health Care System, Portland, OR, funded by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development. The findings and conclusions in this document are those of the author(s) who are responsible for its contents; the findings and conclusions do not necessarily represent the views of the Department of Veterans Affairs or the United States government. Therefore, no statement in this article should be construed as an official position of the Department of Veterans Affairs. No investigators have any affiliations or financial involvement (eg, employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties) that conflict with material presented in the report. i GWI Interventions Evidence Synthesis Program ACKNOWLEDGMENTS This topic was developed in response to a nomination by Karen Block, PhD, Director of Gulf War Research in the Veterans Affairs (VA) Office of Research and Development (ORD) Gulf War Research Program, for the purpose of informing the planning for a state-of-the-art meeting on Gulf War Research and providing guidance for ORD funding priorities in Gulf War research. The scope was further developed with input from the topic nominators (ie, Operational Partners), the ESP Coordinating Center, the review team, and the Technical Expert Panel (TEP). In designing the study questions and methodology at the outset of this report, the ESP consulted several technical and content experts. Broad expertise and perspectives were sought. Divergent and conflicting opinions are common and perceived as healthy scientific discourse that results in a thoughtful, relevant systematic review. Therefore, in the end, study questions, design, methodologic approaches, and/or conclusions do not necessarily represent the views of individual technical and content experts. The authors gratefully acknowledge Robin Paynter, MLIS, and the following individuals for their contributions to this project: Operational Partners Operational partners are system-level stakeholders who have requested the report to inform decision-making. They recommend TEP participants; assure VA relevance; help develop and approve final project scope and timeframe for completion; provide feedback on draft report; and provide consultation on strategies for dissemination of the report to field and relevant groups. Karen Block, PhD Office of Research and Development (ORD) (10P9) – Gulf War Research Program Washington, DC Drew Helmer, MD, MS Deputy Director, Center for Innovations in Quality, Effectiveness and Safety (IQuESt) Houston, TX Technical Expert Panel (TEP) To ensure robust, scientifically relevant work, the TEP guides topic refinement; provides input on key questions and eligibility criteria, advising on substantive issues or possibly overlooked areas of research; assures VA relevance; and provides feedback on work in progress. TEP members are listed below: Peter Rumm, MD, MPH, FACPM Pre-9/11 Era-Program Post-Deployment Health Services Washington, DC Matthew Reinhard, PsyD DC War Related Illness and Injury Study Center Washington, DC ii GWI Interventions Evidence Synthesis Program Lisa McAndrew, PhD NJ War Related Illness and Injury Study Center East Orange, NJ Francis (Fran) Murphy, MD, MPH Sigma Health Consulting Washington, DC area Peter Bayley, PhD CA War Related Illness and Injury Study Center Palo Alto, CA Rebekah (Ryanne) Wu, MD, MHS Durham VA Health Care System Durham, NC Stephen C. Hunt, MD, MPH VA Puget Sound Health Care System Seattle, WA Eva Lee, PhD Georgia Institute of Technology Atlanta, GA Peer Reviewers The Coordinating Center sought input from external peer reviewers to review the draft report and provide feedback on the objectives, scope, methods used, perception of bias, and omitted evidence. Peer reviewers must disclose any relevant financial or non-financial conflicts of interest. Because of their unique clinical or content expertise, individuals with potential conflicts may be retained. The Coordinating Center and the ESP Center work to balance, manage, or mitigate any potential nonfinancial conflicts of interest identified. iii GWI Interventions Evidence Synthesis Program TABLE OF CONTENTS Acknowledgments ......................................................................................................................... ii Abstract .......................................................................................................................................... 1 Executive Summary ...................................................................................................................... 2 Aim ............................................................................................................................................. 2 Methods....................................................................................................................................... 2 Results ......................................................................................................................................... 2 Figure i. Summary of findings .................................................................................................... 3 Conclusion .................................................................................................................................. 4 Abbreviations Table .................................................................................................................... 5 Evidence Report ............................................................................................................................ 9 Introduction ................................................................................................................................... 9 Methods ........................................................................................................................................ 10 Topic Development ................................................................................................................... 10 Search Strategy ......................................................................................................................... 11 Study Selection ......................................................................................................................... 11 Data Abstraction ....................................................................................................................... 13 Quality Assessment ................................................................................................................... 13 Data Synthesis ........................................................................................................................... 13 Rating the Body of Evidence ...................................................................................................