Gulf War Illness: A Systematic Review Of Therapeutic .
Evidence Synthesis ProgramGulf War Illness: A SystematicReview of Therapeutic Interventionsand Management StrategiesApril 2020Prepared for:Department of Veterans AffairsVeterans Health AdministrationHealth Services Research & Development ServiceWashington, DC 20420Prepared by:Evidence Synthesis Program (ESP) CenterPortland VA Medical CenterPortland, ORDevan Kansagara, MD, MCR, DirectorAuthors:Principal Investigator:Michele Freeman, MPHShannon M. Nugent, PhDCo-Investigators:Chelsea K. Ayers, MPHKara A. Winchell, MAAshlyn Press, MPHMaya E. O’Neil, PhDDevan Kansagara, MD, MCR
GWI InterventionsEvidence Synthesis ProgramPREFACEThe VA Evidence Synthesis Program (ESP) was established in 2007 to provide timely and accuratesyntheses of targeted health care topics of importance to clinicians, managers, and policymakers as theywork 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 practiceguidelines 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 inPortland, Oregon. Center Directors are VA clinicians and recognized leaders in the field of evidencesynthesis with close ties to the Agency for Healthcare Research and Quality (AHRQ) Evidence-basedPractice Center Program and Cochrane Collaboration. The Coordinating Center was created to manageprogram operations, ensure methodological consistency and quality of products, and interface withstakeholders. To ensure responsiveness to the needs of decision-makers, the program is governed by aSteering Committee comprised of health system leadership and researchers. The program solicitsnominations 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, ESPCoordinating Center at Nicole.Floyd@va.gov.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 ManagementStrategies. Washington, DC: Evidence Synthesis Program, Health Services Research andDevelopment Service, Office of Research and Development, Department of Veterans Affairs. VA ESPProject #05-225; 2020. Available at: reports.cfm.This report is based on research conducted by the Evidence Synthesis Program (ESP) Center located at the locatedat the Portland VA Health Care System, Portland, OR, funded by the Department of Veterans Affairs, VeteransHealth Administration, Health Services Research and Development. The findings and conclusions in this documentare those of the author(s) who are responsible for its contents; the findings and conclusions do not necessarilyrepresent the views of the Department of Veterans Affairs or the United States government. Therefore, no statementin this article should be construed as an official position of the Department of Veterans Affairs. No investigatorshave any affiliations or financial involvement (eg, employment, consultancies, honoraria, stock ownership oroptions, expert testimony, grants or patents received or pending, or royalties) that conflict with material presentedin the report.i
GWI InterventionsEvidence Synthesis ProgramACKNOWLEDGMENTSThis topic was developed in response to a nomination by Karen Block, PhD, Director of GulfWar Research in the Veterans Affairs (VA) Office of Research and Development (ORD) GulfWar Research Program, for the purpose of informing the planning for a state-of-the-art meetingon 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 consultedseveral technical and content experts. Broad expertise and perspectives were sought. Divergentand conflicting opinions are common and perceived as healthy scientific discourse that results ina thoughtful, relevant systematic review. Therefore, in the end, study questions, design,methodologic approaches, and/or conclusions do not necessarily represent the views ofindividual technical and content experts.The authors gratefully acknowledge Robin Paynter, MLIS, and the following individuals fortheir contributions to this project:Operational PartnersOperational partners are system-level stakeholders who have requested the report to informdecision-making. They recommend TEP participants; assure VA relevance; help develop andapprove final project scope and timeframe for completion; provide feedback on draft report; andprovide consultation on strategies for dissemination of the report to field and relevant groups.Karen Block, PhDOffice of Research and Development (ORD) (10P9) – Gulf War Research ProgramWashington, DCDrew Helmer, MD, MSDeputy Director, Center for Innovations in Quality, Effectiveness and Safety (IQuESt)Houston, TXTechnical Expert Panel (TEP)To ensure robust, scientifically relevant work, the TEP guides topic refinement; provides inputon key questions and eligibility criteria, advising on substantive issues or possibly overlookedareas of research; assures VA relevance; and provides feedback on work in progress. TEPmembers are listed below:Peter Rumm, MD, MPH, FACPMPre-9/11 Era-Program Post-Deployment Health ServicesWashington, DCMatthew Reinhard, PsyDDC War Related Illness and Injury Study CenterWashington, DCii
GWI InterventionsEvidence Synthesis ProgramLisa McAndrew, PhDNJ War Related Illness and Injury Study CenterEast Orange, NJFrancis (Fran) Murphy, MD, MPHSigma Health ConsultingWashington, DC areaPeter Bayley, PhDCA War Related Illness and Injury Study CenterPalo Alto, CARebekah (Ryanne) Wu, MD, MHSDurham VA Health Care SystemDurham, NCStephen C. Hunt, MD, MPHVA Puget Sound Health Care SystemSeattle, WAEva Lee, PhDGeorgia Institute of TechnologyAtlanta, GAPeer ReviewersThe Coordinating Center sought input from external peer reviewers to review the draft report andprovide feedback on the objectives, scope, methods used, perception of bias, and omittedevidence. Peer reviewers must disclose any relevant financial or non-financial conflicts ofinterest. Because of their unique clinical or content expertise, individuals with potential conflictsmay be retained. The Coordinating Center and the ESP Center work to balance, manage, ormitigate any potential nonfinancial conflicts of interest identified.iii
GWI InterventionsEvidence Synthesis ProgramTABLE OF CONTENTSAcknowledgments . iiAbstract. 1Executive Summary . 2Aim . 2Methods. 2Results . 2Figure i. Summary of findings . 3Conclusion . 4Abbreviations Table . 5Evidence Report . 9Introduction . 9Methods. 10Topic Development. 10Search Strategy . 11Study Selection . 11Data Abstraction . 13Quality Assessment. 13Data Synthesis. 13Rating the Body of Evidence . 13Results . 14Key Question 1: What are the benefits and harms of pharmacological and nonpharmacological interventions and management strategies for Veterans with GWI? . 16Medications . 21Nutritional supplements . 22Psychological, exercise, and multi-component interventions . 23Other interventions (acupuncture, CPAP) . 26Key Question 2: Do the effectiveness or harms of the interventions/strategies differ amongsubgroups of Veterans with GWI, such as female Veterans or cases defined by specificcriteria, in comparison with Veterans with GWI overall? . 28Key Question 3: What interventions for GWI have been examined in noncomparative studiesand ongoing/unpublished trials or cohort studies?. 28Summary of Findings. 28Ongoing and Unpublished Studies – Detailed Findings . 31Single-arm Studies with Published Results . 33iv
GWI InterventionsEvidence Synthesis ProgramDiscussion. 34Limitations . 35Heterogeneity . 36Publication Bias . 37Applicability of Findings to the VA Population . 37Implications for VHA . 37Research Gaps/Future Research . 37Conclusions . 39Summary Table. Visual representation of findings . 39References . 41TABLESTable 1. PICOTS by Key Question. 12Table 2. Characteristics of randomized controlled trials of interventions for Gulf War Illness17Table 3. Summary of the effectiveness and strength of evidence from placebo-controlled trialsof medications for treating symptoms of Gulf War Illness. 21Table 4. Summary of the effectiveness and strength of evidence from placebo-controlledtrials of nutritional supplements for treating Gulf War Illness, by symptom domain . 23Table 5. Summary of the effectiveness and strength of evidence from trials ofpsychological, exercise, or multi-component interventions for treating GWI, bysymptom domain. 25Table 6. Summary of the effectiveness and strength of evidence from trials ofacupuncture and CPAP in Veterans with Gulf War Illness . 26Table 7. Interventions for GWI in ongoing/unpublished clinical trials and single-arm studies 29Table 8. Risk of bias in trials of interventions for Gulf War Illness . 55Table 9. Results for physical health, pain, and fatigue outcomes in intervention trials for GulfWar Illness . 57Table 10. Results for cognitive, mental health, PTSD symptoms, and global outcomes inintervention trials for Gulf War Illness . 61Table 11. Results for gastrointestinal symptoms and sleep outcomes in intervention trials forGulf War Illness . 66Table 12. Adverse events in published intervention studies for Gulf War Illness . 68Table 13. Details of ongoing and unpublished controlled trials of interventions/managementstrategies for Gulf War Illness . 69Table 14. Details of single-arm studies of interventions/management strategies for Gulf WarIllness . 80Table 15. Available results of unpublished randomized controlled trials of interventions forGulf War Illness . 81v
GWI InterventionsEvidence Synthesis ProgramTable 16. Results of single-arm studies of interventions/management strategies for Gulf WarIllness . 83FIGURESFigure 1. Conceptual framework . 10Figure 2. Literature Flow Chart . 14Figure 3. Frequency of intervention categories* among published (KQ1) andunpublished (KQ3) studies of treatments for GWI . 35Appendix A. Search Strategies . 46Appendix B. Study Selection . 52Appendix C. Quality Assessment Criteria . 54Appendix D. Data Supplement . 57APPENDIX E. Peer Review Comments/Author Responses . 85vi
GWI InterventionsEvidence Synthesis ProgramABSTRACTAim: We conducted a systematic review of therapeutic interventions for Gulf War Illness (GWI)to evaluate effectiveness and harms and identify potentially promising treatments.Methods: We searched electronic databases, trial registries, and reference lists throughSeptember 2019 for randomized and non-randomized controlled trials and cohort studies directlycomparing interventions for Veterans with GWI to each other, placebo, or usual care. Weabstracted data on study design, demographics, interventions, and outcomes. Two reviewersindependently assessed studies for inclusion, quality, and strength of evidence using prespecified criteria. We resolved discordant ratings by discussion and consensus.Results: We identified 12 RCTs, each of which examined a different intervention for GWI. Wefound moderate-strength evidence that cognitive behavioral therapy (CBT) and exercise,separately and in combination, were associated with improvements in several GWI symptomdomains. There was low-strength evidence of benefit from 2 mindfulness-based interventionsand Continuous Positive Airway Pressure (CPAP). Mindfulness-based stress reduction improvedpain, cognitive functioning, fatigue, depression, and posttraumatic stress disorder (PTSD), whilemind-body bridging improved fatigue, depression, PTSD, and sleep, although pain and otheroutcomes did not improve. CPAP improved overall physical health, pain, cognitive functioning,fatigue, mental health, and sleep quality in a small study of Veterans with sleep-disorderedbreathing and GWI. We found moderate-strength evidence that doxycycline is ineffective forGWI in mycoplasma DNA-positive Veterans and increases the risk of adverse effects comparedwith placebo. We also found 33 ongoing, single-arm pilot, or unpublished studies examining avariety of interventions.Conclusion: There is moderate-strength evidence of benefit from CBT and exercise, and lowstrength evidence of benefit from 2 distinct mindfulness-based interventions as well as CPAP.Doxycycline was ineffective and associated with harms (moderate-strength evidence). Emergingevidence examines a wide array of treatments. Larger, more rigorous studies are needed toreproduce and characterize positive findings.1
GWI InterventionsEvidence Synthesis ProgramABBREVIATIONS an AmericanAllied and Complementary Medicine DatabaseBrief Assessment Checklist for AdolescentsBeck Depression Inventorybis in dieBrief Pain InventoryBrief Pain Inventory-Short FormBrief Symptom InventoryBowel Symptom ScaleBrief Visuospatial Memory Test-RevisedClinician-Administered PTSD Scale for DSM-5Complete Blood CountCognitive Behavioral TherapyCognitive Behavioral Therapy for InsomniaCochrane Central Register of Controlled TrialsCenters for Disease Control and PreventionCongressionally Directed Medical Research ProgramsChronic Disease Self-Management ProgramCochrane Database of Systematic ReviewsCenter for Epidemiological Studies-Depression ScaleCognitive Failures QuestionnaireChalder Fatigue ScaleChronic Fatigue SyndromeConfidence
comparing interventions for Veterans with GWI to each other, placebo, or usual care. We abstracted data on study design, demographics, interventions, and outcomes. Two reviewers independently assessed studies for inclusion, quality, and strength of evidence using pre-specified criteria. We
Uranium, Sarin, Pyridostigmine Bromide, and Vaccines. July 26, 2001 Treating Symptoms and Syndromes. August 20, 2004 Gulf War and Health: Updated Literature Review of Sarin. September 12, 2006 Gulf War and Health: Volume 4. Health Effects of Serving in the Gulf War. At least 3
Bockus, John Civil War 0-48 Knapp, Leonard Civil War 0-62 Bryson, Frank T. Civil War 0-6 Lampson, G. W. Civil War 0-25 Burkley, John I. Civil War 0-65A Martin, Jacob A. Civil War 0-49 Carr, Asa M. Civil War 0-39 Martin, Pembrooke Civil War 0-9A Carr, Julius Civil War 0-39 Mather, Jonathan War of 1812 0-78
2 VA History in Brief Table of Contents Chapter Page . 1 Colonial era through the Civil War 3 2 World War I era 7 3 World War I bonus march 9 4 Veterans Administration established, World War II, GI Bill 12 5 Post World War II through the Korean War 15 6 Vietnam War era, Agent Orange 18 7 Post-Vietnam era 22 8 VA becomes a Cabinet-level department; Persian Gulf War 26
1.3 This Guide 6 2. Understanding mental illness 7 2.1 About mental illness 7 2.2 Facts about mental illness 7 3. Managing mental illness in the workplace 9 3.1 Effective communication strategies 9 3.2 Reasonable adjustments 11 3.3 Examples of reasonable adjustments to address the effects of a worker's mental illness in the workplace 13
Gulf of Tonkin War begins Escalates troop levels . Gulf of Tonkin Incident USS Maddox attacked off of coast of North Vietnam . Causes of the war Long Term Failed French effort to recolonize Vietnam after World War II, . Tonkin Gulf Inc
politics of the Arab world. In the Maghreb, U.S. and Gulf state interests overlap to the extent that all players want stability, but each state has its own definition of what stability means. The U.S. and the Gulf states all support the Moroccan and Algerian regimes, but intra-Gulf rivalries are helping destabilize Libya, where different Gulf-
Dr. George DeMartino Dr. Philip Thomas Univ of Texas Southwestern 3:00 – 3:30 A neuronal cell culture model for the study of Gulf War illness Dr. Ilya Bezprozvanny Univ of Texas Southwestern 3:30 – 3:45 Break 3:45 – 4:45 Approaches to assessing treatments for Gulf War illnesses: the Southwestern experience Dr. Robert Haley 4:45 – 5:45
light on the consequences of the war on the political, economic, social, and humanitarian levels. Finally, the true intentions of the war are speculated. Keywords –Political Science, Warfare, Iraq War 2003, Global War on Terrorism I. INTRODUCTION The Iraq war, sometimes known as the Third Gulf War, began on March 20, 2003 with the invasion of
