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Management Brief No. 171

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Management eBriefs
Issue 171 May 2020

The report is a product of the VA/HSR Evidence Synthesis Program.

Gulf War Illness: A Systematic Review of Therapeutic Interventions and Management Strategies

As many as 250,000 former service members may suffer from Gulf War Illness (GWI). While research related to GWI has been ongoing since the 1990's–by VA, the Department of Defense (DoD), and other institutions–there has been a recent expansion of studies of treatments and management strategies for GWI. Therefore, an updated, systematic evidence review that focuses on the treatment of GWI in Gulf War Veterans is needed to understand this emerging body of evidence and assist VA leadership in developing and funding future clinical and research priorities.

After the 1990-1991 conflict in the Persian Gulf, many Gulf War Veterans began reporting multiple, diverse unexplained symptoms including, but not limited to systemic pain, fatigue, flu-like symptoms, and difficulty with memory and/or concentration. These symptom clusters were initially described by some outside VA as Persian Gulf War Syndrome, medically unexplained symptoms, or Chronic Multi-symptom Illness by VA and DoD; most recently, the term Gulf War Illness (GWI) is used.

This systematic review sought to identify therapeutic interventions for Gulf War Illness, evaluate the effectiveness and harms of these interventions, and identify potentially promising treatments. Investigators with VA’s Evidence Synthesis Program (ESP) Center in Portland, OR searched the literature, including Ovid MEDLINE, Ovid PsycINFO, Ovid EBM Reviews (Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), CINAHL, and the Allied and Complementary Medicine Database (AMED) through September 17, 2019. After reviewing 4,621 citations (155 articles received full text review), they included 45 studies that discussed 12 randomized controlled trials (RCTs), each of which examined a different intervention for GWI.

Summary of Findings

The following potential beneficial effects were identified:

  • A combination of cognitive behavioral therapy (CBT) and exercise or exercise alone improved several GWI symptoms domains including cognitive functioning, fatigue and overall mental health (moderate-strength evidence).
  • Mindfulness-based stress reduction improved pain, cognitive functioning, fatigue, depression, and PTSD (low-strength evidence).
  • Mind-body bridging – another type of mindfulness intervention – improved fatigue, depression, PTSD, and sleep, though it did not improve overall physical or mental health, pain, or cognitive functioning (low-strength evidence).
  • Continuous Positive Airway Pressure (CPAP) improved overall physical health, pain, cognitive functioning, fatigue, mental health, and sleep quality in a small study of Veterans with sleep-disordered breathing and GWI (low-strength evidence).

Moderate-strength evidence also suggested that doxycycline is likely to be an ineffective treatment and is associated with harms.

Most of the evidence base consists of small studies each examining a different intervention. Heterogeneity of case definitions and outcomes measured limited selected outcomes. The findings described are likely to change as more research is conducted. For example, there are 33 ongoing, single-arm pilot, or unpublished studies examining a variety of interventions; some of these studies will help strengthen the evidence base for interventions that have already been examined on a small scale (i.e., CBT and mindfulness-based stress reduction). However, many of these studies examine interventions that are both different from each other and different from interventions that have been studied before. While this approach may help identify potentially promising interventions, the variety of treatments examined will make it challenging to develop enough of an evidence base to guide clinicians about which treatments are most likely to be effective in clinical practice and which treatments should be avoided.

Implications for VA

The findings of this report can help inform VA priorities for future funding and clinical inquiry. VA is in a unique position to design novel approaches to more quickly test promising interventions in hybrid efficacy/effectiveness trials leveraging its national system of integrated primary, specialty and mental healthcare, which would accelerate the availability of potential beneficial treatments for Veterans with Gulf War Illness. There are several promising interventions including mindfulness-based approaches, CBT, and exercise (separately or together), and the use of a CPAP among those with sleep-disordered breathing and Gulf War Illness.

Research Gaps/Future Research

Research gaps and future ways to improve the evidence base include:

  • Consolidation of intervention work, replicating promising interventions and conducting studies of a hybrid design to assess the effectiveness and feasibility of implementation of promising interventions in VA settings;
  • Development of a single case definition that considers the onset of other chronic health conditions in this aging population; and
  • Development and use of consistent outcome measures capable of assessing the depth and breadth of GWI symptoms, considering the severity of illness to differentiate those with severe and less severe disease, and measuring longitudinal change in symptom severity.

Further, larger and more rigorous studies are needed to reproduce and characterize positive findings – and to determine efficacy for multiple endpoints.

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.

To view the full report, go to on the intranet only at (VA network access only).

ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

This report is a product of VA/HSR&D's Evidence Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers –; and to disseminate these reports throughout VA.

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