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Management Brief No. 176

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Management eBriefs
Issue 176 October 2020

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

Biological Measures and Diagnostic Tools for Gulf War Illness: A Systematic Review

The setting of the 1990-1991 conflict in the Persian Gulf was fraught with potential exposure to multiple toxins and stressors, including environmental and chemical exposures (i.e., solvents, depleted uranium, excessive heat, oil-well fire smoke, pesticides, nerve agents and their prophylaxis, and vaccines) and psychological stressors associated with a combat setting (i.e., separation from family, uncertainty about presence of chemical and biological agents, and witnessing dead or wounded soldiers and citizens). After the conflict, many Gulf War Veterans began reporting numerous unexplained symptoms which were eventually defined as Gulf War Illness (GWI). The proportion of Gulf War-deployed Veterans who meet case criteria for GWI is approximately 34% to 50%, depending on which definition of GWI is used. Yet these definitions remain disputed and outdated. The identification of promising biological markers could help refine the illness definitions; better detect, predict, or distinguish subgroups of GWI; and ultimately lead to the development of biologically plausible treatments.

Gulf War Illness is a chronic multi-symptom illness comprised of a wide range of systemic symptoms and functional impairments, including fatigue, headaches, joint pain, indigestion, insomnia, dizziness, respiratory disorders, and memory problems.

This systematic review sought to catalogue studies (both published and unpublished/ongoing) of validated biological tests for diagnosing GWI, and any associations between biological measures and the presence of GW, which may provide insight to biomarkers that are potentially promising to examine further for diagnostic validity. Investigators with VA’s Evidence Synthesis Program (ESP) Center in Portland, OR searched the literature, including Ovid MEDLINE, and Ovid PsycINFO, and Ovid EBM Reviews (Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials) through February 2020. After reviewing 2,102 citations (270 articles received full text review), investigators included 32 completed and 24 ongoing or unpublished studies of the associations between GWI and biological measures, most of which targeted the central nervous and immune systems. In their search, investigators identified no studies designed to validate diagnostic tests for GWI.

Summary of Findings

Investigators identified no existing validated biological tests to determine GWI case status. This may be, in part, because the case definition for GWI is still debated. In the absence of a gold standard definition or diagnostic test, the determination of biological measures to distinguish a case from a non-case is challenging.

Most studies could be characterized as “biomarker discovery” studies and were largely designed to shed light on the potential mechanisms of GWI. Biological measures within the immune and central nervous systems have more often been investigated for their potential relationship with GWI. The literature also suggests other avenues of inquiry in upcoming studies, such as the gut microbiome. Importantly, this review revealed that existing studies are insufficient for determining promising biomarkers due to the extent of heterogeneity in biological measures across studies, inadequate comparator groups, and several other methodological limitations.

Research Gaps/Future Research

Future studies that employ ideal control groups, build upon findings of existing studies, and otherwise apply rigorous methodological practices and reporting specifically appropriate for investigating potential biomarkers would contribute to the establishment of a base of targeted, highly reliable studies from which lines of investigation could grow. This review also identified ongoing or upcoming studies related to GWI biological measures that are likely to contribute to our knowledge of GWI, such as:

  • epigenetic DNA changes in Veterans with GWI,
  • effects of exposure to cholinergic compounds,
  • abnormalities in tau – a cytoskeletal protein;
  • probability scores of case qualification at the individual level using a computerized diagnostic system that incorporates multiple biological measure data, and
  • a computer-based diagnostic system for identifying brain-immune interactions in GWI.

GWI treatments also are being studied simultaneously, including an upcoming trial of an antioxidant – Coenzyme Q10 (CoQ10).

Gean E, Ayers CK, Winchell KA, Freeman M, Press AM, Paynter R, Kansagara D, and Nugent SM. Biological measures and Diagnostic Tools for Gulf War Illness - A Systematic Review. 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 (If you have intranet access, copy and paste the link into your browser.)

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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