The Antibiotic Treatment Trial of Gulf War Veterans' Illnesses

Abstract

Many veterans who were deployed to the Persian Gulf during the 1990–1991 Gulf War developed multiple unexplained symptoms such as pain, fatigue, and neurocognitive problems. This constellation of symptoms has been termed Gulf War Veterans' Illnesses (GWVI). Although there is no proven explanation for the cause of GWVI, one fairly widespread explanation is systemic Mycoplasma fermentans infection. The Antibiotic Treatment Trial of GWVI is a randomized placebo-controlled trial to determine whether a 1-year course of doxycycline treatment in deployed Gulf War veterans with GWVI and testing as Mycoplasma species positive will improve their overall functional status as measured by the Physical Component Summary of the SF-36V questionnaire. The study of a multisymptom illness such as GWVI is complicated by the nonspecific nature of the illness, the unknown etiology, and the lack of a widely accepted outcome measure. The presumption of mycoplasma infection raises concerns regarding the methodology for determination of mycoplasma infection, the choice of treatment, and the duration of treatment. However, such a presumption allows the formulation of a clear testable hypothesis that can be tested with treatments with known rates of adverse events and known activity against Mycoplasma species. This paper describes the major issues faced by the investigators during planning, the study design, the patient screening results, and the baseline characteristics of the study patients. There were 2712 patients screened for study entry at 26 Department of Veterans Affairs and two Department of Defense medical centers. Of these, 491 met all study entry criteria and were randomized to either 1 year of doxycycline (200 mg/day) or 1 year of placebo. All patients were seen monthly during treatment and at 6 months after the end of treatment. Study patients had a mean age of 41 years and were mostly male (86%), white (64%), married (68%), and employed full-time (71%).

Introduction

In 1990 and 1991, the United States deployed approximately 700,000 troops to the Persian Gulf during the Gulf War. There were relatively few combat- and noncombat-related injuries and diseases during this conflict in comparison with previous military campaigns. Most veterans of this conflict who became ill and received care from the Departments of Veterans Affairs (VA) or Defense (DoD) had diagnosable and treatable conditions 1, 2, 3. However, the symptoms of approximately 15–20% of those with illnesses have not been explained, and this constellation of symptoms has been termed Gulf War Veterans' Illnesses (GWVI) 4, 5, 6. While the acronym GWVI will be used to describe this constellation of symptoms occurring in many veterans of the Gulf War, similar illnesses have been noted after nearly every major conflict [7]. More importantly, similar disorders of symptom aggregation, such as fibromyalgia, chronic fatigue syndrome (CFS), and multiple chemical sensitivity (MCS), occur at a high background rate in the general population 3, 8, 9, 10, 11, 12.

Although several explanations have been offered as to the cause of illnesses among Gulf War veterans, none of the putative etiologic agents or conditions is currently supported by conclusive empirical or scientific evidence. Research into causes has encountered numerous problems obtaining valid measurements of the many plausible exposures related to Gulf War service. One explanation that has received widespread attention from Gulf War veterans and their advocates is systemic Mycoplasma fermentans infection. Nicolson and colleagues have been active proponents of this hypothesis 13, 14, 15, and based on their preliminary data some clinicians have been using doxycycline to treat GWVI. While additional data justifying the Mycoplasma fermentans hypothesis might have been useful, such as controlled studies of mycoplasma infection in deployed and nondeployed veterans and phase II studies of the effects of antibiotics on patients' symptoms, these additional studies would have taken years to complete. Since it was almost 10 years since the Gulf War exposure and these patients were still ill, the VA decided to proceed with a study of antibiotic treatment for GWVI.

The VA Antibiotic Treatment of Gulf War Veterans' Illnesses Trial is a 30-month, prospective, randomized, double-blind, placebo-controlled clinical trial that started in May 1999 and ended in October 2001. Its purpose is to determine if antibiotic treatment (i.e., doxycycline) directed against Mycoplasma species improves symptoms in deployed Gulf War veterans with GWVI. Gulf War veterans with GWVI who met all entry criteria and gave informed consent were randomized to receive either 200 mg/day of doxycycline or placebo. All participants were treated for 12 months with an additional 6 months of follow-up to determine relapse rates. There were 491 Gulf War veterans entered into the study at 26 VA and two DoD medical centers.