A Working Plan
For Research on
Persian Gulf Veterans' Illnesses
Persian Gulf Veterans Coordinating Board


FirstRevision
November 1996

 

 


TABLE OF CONTENTS

 

PREFACE 1
EXECUTIVE SUMMARY 3
INTRODUCTION 9
Background 9
The Role of Research 10
Research Management and Coordination 10
Purpose of the Working Plan 11
Organization of this Document 11
GENERAL FINDINGS FROM PANEL ASSESSMENTS 13
Defense Science Board 13
NIH Technology Assessment Workshop 14
National Academy of Sciences/Institute of Medicine/Medical Follow-up Agency 14
Presidential Advisory Committee on Gulf War Veterans’ Illnesses (PAC) 15
FRAMING THE PROBLEM 17
Exposures 18
Infectious Agents 20
Smoke from Oil Well Fires and Oil Spills 21
Other Petroleum Products 21
Other Occupational Exposures 22
Chemical and Biological Warfare Agents 23
Vaccines 25
Pyridostigmine Bromide 26
Psychophysiological Stressors of War 26
Troop Locations 27
Health Outcomes 27
Non-specific Symptoms/Symptom Complexes 29
Immune Function 30
Reproductive Health Outcomes 30
Genitourinary Disorders 32
Pulmonary Function Abnormality 32
Neuropsycholgical and Neurological Outcomes 34
Psychological/Psychiatric Outcomes 37
Infection 39
Cancer/Neoplastic Disease 40
Mortality Outcomes 41
SUMMARY AND RECOMMENDATIONS 43
REFERENCES 47
   
PERSIAN GULF VETERANS’ ILLNESSES RESEARCH DATABASE
Appendix

PREFACE

Persian Gulf War veterans report a variety of symptoms and illnesses that may have been caused by their military service. Although the Departments of Veterans Affairs (VA) and Defense (DoD) have taken important steps to ensure that these veterans have access to quality medical care, there is an urgent need to increase understanding of the nature and extent of these illnesses, and their potential connection to service in the Persian Gulf.

The overwhelming majority of Persian Gulf veterans who have come to VA or DoD for medical care have been found to have common conditions and have received appropriate treatment for their problems. However, similar to the general civilian population, some veterans have symptoms that are difficult to explain using current diagnostic criteria for illnesses. A critical unresolved issue is whether they are experiencing these symptoms at a higher rate than comparable non-Persian Gulf war veterans. In addition, many veterans have questioned whether the illnesses that are common and diagnosable are etiologically linked to their service in the Persian Gulf conflict. While many medical questions have been answered with existing knowledge of the Persian Gulf veterans’ experience, others require scientific research.

The VA, DoD, Department of Health and Human Services (HHS), and Environmental Protection Agency (EPA), through the Persian Gulf Veterans Coordinating Board (PGVCB), have led the way in the conduct of research on Persian Gulf veterans’ illnesses. In 1995 it was apparent that the scope of the research issues necessitated the development of a working plan to help the Persian Gulf Veterans Coordinating Board coordinate federally-sponsored research in a way that all the relevant research issues would be targeted but unnecessary duplication would be avoided. This document is the first revision of the original 1995 A Working Plan for Research on Persian Gulf Veterans’ Illnesses (PGVCB, 1995). Because research, by its nature, often leads to unexpected findings, as well as refinement in thinking about specific topics, the original plan was designed to be flexible and evolve over time. New research findings in the past year and other information that has come to our attention, as well as the initiation of new research, have led to the need for a revision of the Working Plan. It is anticipated that the Working Plan will undergo further revisions in the future.

The original research plan and subsequent revisions attempt to balance the need for specific, targeted research directions, with the awareness that successful research, fostered by sound research questions, arises from the minds of independent scientists in research laboratories. Therefore, the Working Plan sets the broad research areas in which it is believed investment will most likely bring new and useful knowledge.

Although the Working Plan is primarily intended to guide federal decision makers in establishing research priorities, it is also meant to provide information to members of Congress, the scientific community, the public and, importantly, the veterans of the Persian Gulf conflict, about the manner in which the federal government is carrying out this important research.

In the interest of completeness, this revision of the Working Plan includes material from the original 1995 Working Plan. New research information is woven into the main body of this revised Working Plan.

It is important to note that the Working Plan is an essential component of research, and that research is only one element of a broader strategy aimed at addressing the health problems and concerns of Persian Gulf veterans and their families. These elements include:

 

MEDICAL CARE

Providing appropriate medical care has been a top priority of VA and DoD. The two departments have acted aggressively to ensure the delivery of high quality medical care to Persian Gulf veterans.

RESEARCH

Research, which is the subject of the present document, is indispensable to the improvement of medical care for Persian Gulf veterans, the institution of appropriate interventions, and to the formation of a firm basis for compensation.

COMPENSATION

VA and DoD continue to work diligently to ensure prompt and appropriate compensation of Persian Gulf veterans disabled by their military service.

EDUCATION AND OUTREACH

Persian Gulf veterans and their health care providers must have access to the latest information on medical care, compensation, and research. This information will enable veterans to make sound judgments about their own health status, and to know how and where they can seek assistance. It will also enable physicians, and other health care providers, to provide state-of-the art diagnoses and treatment to veterans.

Finally, to help ensure that the US Government is doing everything possible to determine the causes and provide care to those who are ill, the President established a Presidential Advisory Committee on Gulf War Veterans’ Illnesses that began its work in August 1995. This Advisory Committee is reviewing and providing recommendations on the full range of US Government activities on this important issue. Its final report is expected in December, 1996.

Through the continued implementation of the Working Plan, in conjunction with the other components of the overall strategy, it is hoped that confident, reliable answers to the concerns of Persian Gulf veterans can be obtained as quickly as possible and with maximal efficiency.

 

Kenneth W. Kizer, M.D., M.P.H.

Under Secretary for Health

Department of Veterans Affairs


1. EXECUTIVE SUMMARY

  Since veterans returning from the Persian Gulf first started to report symptoms and illnesses in late 1991, a significant number of clinical evaluation and research activities have been undertaken. In 1995 the magnitude of the research effort required implementation of a comprehensive plan. This resulted in publication by the Persian Gulf Veterans Coordinating Board (PGVCB) of A Working Plan for Research on Persian Gulf Veterans’ Illnesses (PGVCB, 1995) on August 5, 1995. Since that time the number of research programs investigating Persian Gulf veterans’ illnesses has increased substantially. Some research programs have begun to produce results. New information about potential exposures to chemical weapons has become available. These changes in the context within which research is conducted have necessitated this revision of the 1995 Working Plan. As with the original document, the current plan maps out the course by which the following goals can be pursued:

Establish the nature and prevalence of symptoms, diagnosable illnesses, and unexplained conditions among Persian Gulf veterans in comparison to appropriate control groups;

Identify the possible risk factors for any illnesses, beyond those expected to occur, among Persian Gulf veterans;

Identify appropriate diagnostic tools, treatment methods, and prevention strategies for any excess illness conditions found among Persian Gulf veterans.

The Working Plan is coordinated by the Department of Veterans Affairs (VA) in conjunction with the Persian Gulf Veterans Coordinating Board. The research conducted under the aegis of this plan is executed by various departments and agencies, inluding VA, DoD, and HHS. The Research Working Group (RWG) of the PGVCB is the primary research coordinator and is charged with assessing the state and direction of research; identifying gaps in factual knowledge and conceptual understanding; identifying testable hypotheses; recommending research directions for participating agencies; reviewing research concepts as they are developed; collecting and disseminating scientifically peer-reviewed research information; and ensuring that all research conducted under the umbrella of the RWG undergoes appropriate scientific peer-review, and that the results of peer-review lead to appropriate actions by the sponsoring agencies.

Establishment of the prevalence of symptoms and illnesses in comparison with appropriate control populations is an essential base upon which additional research depends. If Persian Gulf veterans are experiencing symptoms and illnesses that are in excess of expectations for such a population, further research into risk factors can then be approached by separating the overall investigation into two categories: analysis of health outcomes and analysis of exposures. These analyses need to be conducted in a manner that defines the association between exposures and outcomes.

Based on the findings of three scientific panels -- the Defense Science Board Task Force (DSB, 1994); the NIH Technology Assessment Workshop (NIH, 1994); and the Institute of Medicine (IOM, 1995) -- and other current information, exposures to psychological war stressors, Leishmania tropica (L. tropica), petroleum products, insecticides and insect repellents [possibly in combination with pyridostigmine bromide (PB)], are important to consider if any excess illnesses are found. Vaccines, chemical agents resistant coating (CARC) paint, depleted uranium (DU) and smoke from oil well fires have been considered by the scientific panels as unlikely sources of Persian Gulf veterans’ illnesses.

A key component of the 1995 Working Plan was an assessment of current knowledge and research on Persian Gulf veterans’ illnesses. This assessment, along with guidance from the aforementioned scientific panels, led to the identification of the following areas of inquiry for which significant gaps in knowledge existed at that time:

Information on the prevalence of symptoms, illnesses, and/or diseases within other coalition forces;

Information on the prevalence of symptoms, illnesses, and/or diseases within indigenous populations within the Persian Gulf area including Saudi Arabia and Kuwait;

Information on the prevalence of adverse reproductive outcomes among Persian Gulf veterans and their spouses;

Simple and sensitive tests for L. tropica infection that could lead to quantification of the prevalence of L. tropica infection among Persian Gulf veterans; and

Information on the long-term, cause-specific mortality among Persian Gulf veterans.

In June of 1995 DOD issued a Broad Agency Announcement (BAA) soliciting research proposals to investigate Persian Gulf veterans’ illnesses. Proposals were sought from federal and non-federal scientists who were encouraged to broadly direct their efforts to epidemiology, clinical research, and research on pyridostigmine bromide. The solicitation was given additional focus by the research gaps identified in the 1995 Working Plan. In June 1996, DoD and VA announced the award of the first 12 of 15 new research grants as an outcome of the original BAA. These were selected on the basis of scientific merit by an independent scientific review panel, and on program relevancy derived from the list of research gaps. These new projects, and other research initiatives in 1995/1996, address most of the gaps identified in the 1995 Working Plan.

Events in 1995/1996, including the addition of new research, results of ongoing research, and new information about exposures during the Persian Gulf War, form the basis of a new assessment of knowledge and research.

In the 1995 Working Plan it was stated that lacking confirmatory evidence of exposure to chemical or biological weapons, research on chemical and biological weapons should not be undertaken. Since then, there have been reports of potential exposures resulting from allied bombing of two Iraqi chemical weapons facilities, and the destruction by US ground forces of a munitions bunker and storage pit that United Nations inspection teams have concluded contained sarin and cyclosarin. This new information raises concern about chemical weapons exposure, and leads to recommendations for more research on the long-term effects of low-level exposures to chemical agents, including basic research and epidemiologic investigations.

Epidemiologic studies are now beginning to provide information about the prevalence of self-reported symptoms, illnesses, and self-reported exposures among Persian Gulf veterans, and their spouses and children. Furthermore, clinical epidemiology and basic research are also beginning to yield results relevant to the determination of potential pathologies and their risk factors underlying the symptoms.

Findings from some of these studies indicate the following:

Some groups of Persian Gulf veterans have self-reported an excess of symptoms in comparison with non-deployed veterans of the same era (Kaiser et al, 1995; CDC, 1995). A connection between symptoms and a specific disease pathology or pathologies has not been identified.

Based on VA and DoD mortality studies to date (Kang and Bullman, 1996; Writer et al, 1996), there does not appear to be an excess of disease-specific deaths in Persian Gulf veterans when compared to veterans of the same era.

A Navy study of hospitalizations (Gray and Coate, 1996a,b) indicates that, at least among active duty personnel, the rate of hospitalizations of Persian Gulf veterans does not exceed their non-deployed counterparts. This suggests that Persian Gulf veterans are not experiencing an excess of illnesses of a severity that would lead to hospitalization.

One focused study of a small cohort of Persian Gulf veterans (Penman et al, 1996) and one study of military hospitalizations (Cowan et al, 1995) did not uncover an excess of birth defects among their offspring. Several ongoing and new epidemiologic studies are investigating pregnancy and birth outcomes. Results from these studies will begin to be available in 1997.

A DoD study (US Army, 1995) of the interaction of PB, DEET, and permethrin in high dose, orally-exposed rats provides evidence in an animal model for synergistic effects of these compounds. Synergism is also suggested in a study of neurotoxicity in chickens at lower, though still acutely toxic, doses (Abou-Donia et al, 1996). This research suggests the need for further exploration of the potential interactive effects of these compounds at doses of greater relevance to humans. Research currently being conducted by DoD and VA will attempt to further address issues of PB and other compounds that could have interacted with it.

A single study focusing on high-level central nervous system processing (Goldstein et al, 1996) found no clinically significant neuropsychological differences between a symptomatic, self-selected group of Persian Gulf veterans and a control group, with psychological stress accounting for the small deficits that were detected.

A study focusing on the peripheral nervous system (Jamal et al, 1996) in 14 self-selected Persian Gulf veterans found small, but significant differences in 3 of 22 tests of peripheral nerve function related to large fiber peripheral nerve function and thinly myelinated small fiber function.

The epidemiologic investigations cited above were generally conducted in narrowly defined cohorts not necessarily representing the entire population of Persian Gulf veterans. Therefore, the ability to generalize beyond those studies to larger populations of Persian Gulf veterans is limited. However, results from ongoing epidemiological studies, when completed and combined with these findings, will facilitate broader generalizations.

In addition to new research findings and new research initiatives in the United States, the US Government is coordinating its research effort with Great Britain and Canada, each of whom participated in the Persian Gulf War as coalition partners. VA scientists are also actively collaborating with researchers in Denmark and Japan. Denmark participated in the Persian Gulf War as a coalition partner. The collaboration with Japanese scientists involves follow-up research on individuals exposed to sarin in the Tokyo subway terrorist incident in 1995.

Emerging findings from ongoing research in the past year, and new factual information on the potential for chemical weapons exposure in southern Iraq in 1991 lead to the following specific, near-term recommendations for additional research:

Follow-up of the mortality experience of Persian Gulf veterans, encompassing cause-specific mortality, at appropriate future time-points;

More longitudinal follow-up studies of the health of Persian Gulf veterans, including those with illnesses that are difficult to diagnose;

Critical peer-review of models used to predict exposure concentrations of environmental pollution (such as the Kuwait oil well fires) and chemical warfare agents (such as the demolition of weapons storage sites at Khamisiyah in March, 1991 and aerial bombing of chemical weapons facilities during the air war);

Assessment of the potential for clinical investigations of the health status of the service members in the vicinity of Khamisiyah when weapons bunker 73 and the storage pit were detonated in March, 1991. If deemed possible, such clinical investigations should be carried out.

Additional research on health-related issues arising from the Persian Gulf experience but with potential for more general applicability to future conflicts is also recommended, including:

Investigation of the risk factors for the development of stress-related disorders including, but not limited to, post-traumatic stress disorder (PTSD);

Investigation of the risk factors responsible for the observed excess mortality due to external causes (e.g., motor vehicle accidents) in veterans of all wars and conflicts;

Exploration of the development of practical, sensitive, and specific biomarkers of exposure to chemical agents, including organophosphate nerve agents and vesicants such as sulfur mustard.

Toxicological and, where feasible, epidemiological research on the potential for long-term health effects resulting from low-level, sub-clinical exposures to chemical agents, particularly organophosphate agents such as sarin;

Development of a strategic plan for research into the potential long-term health consequences of exposure to low-levels of chemical warfare agents;

If a simple, sensitive and specific, as well as economic, test for L. tropica infection becomes available, seroepidemiologic studies may be undertaken in Persian Gulf veterans. Indeed, when feasible and practical, sera of veterans should be stored in expectation of the possibility for such studies. Despite the declining importance of L. tropica as a risk factor in Persian Gulf veterans, continued research on tests for L. tropica infection are valuable for potential future deployments. ;

It is further recommended that a contextual framework for the results of completed and ongoing studies be provided to develop approaches for the collective interpretation of research results. A meeting of researchers should be organized to provide such a framework.

Because of the changing nature of scientific research, and the acquisition of new factual information, this plan will likely undergo additional revisions in the future.


2. INTRODUCTION

2.1 BACKGROUND

A wide variety of symptoms and illnesses began to be reported by veterans returning from the Persian Gulf conflict in late 1991. The initial response to this problem appropriately involved descriptive studies including:

Clinical evaluations;

Disease outbreak and cluster investigations;

Population health surveillance;

Initial exposure inventory and assessment;

Troop location.

The response included establishing the Department of Veterans Affairs (VA) Persian Gulf Registry Health Examination Program ("Persian Gulf Registry") and Persian Gulf Referral Centers, and the Department of Defense (DoD) Comprehensive Clinical Evaluation Program (CCEP). These major clinical undertakings resulted in appropriate medical care and allowed the systematic collection of clinical, and other descriptive data, regarding the health of Persian Gulf veterans that would aid in treatment of veterans and active duty service members.

As of October 1996, over 62,000 Persian Gulf veterans had completed the VA registry examination and had their examination. Of veterans in the registry with one or more symptoms, 77% received medical diagnoses from VA clinicians. The DoD CCEP reveals a similar pattern of findings among the more than 18,500 participants who had completed the examination as of the same time (DoD, 1996)

Overall, the VA Persian Gulf Registry and the CCEP have identified a wide spectrum of overlapping symptoms involving multiple organ systems. As of May 1996, the most commonly reported symptoms from the VA Persian Gulf Registry include:

SYMPTOM

FREQUENCY

Fatigue

20%

Skin rash

18%

Headache

18%

Muscle/Joint pain

17%

Memory loss

14%

Shortness of breath

8%

Sleep disturbances

6%

Diarrhea and other GI symptoms

5%

Chest Pain

4%

In the initial stages of the search for a cause of these symptomatic conditions, attention was brought to the multitude of environmental, occupational, and biological exposures that may have been experienced by many of the troops. When combined with the unique conditions of a rapid, large-scale deployment, it was evident that a quantitative understanding of the nature of these exposures would be needed along with better understanding of the illnesses.

2.2 THE ROLE OF RESEARCH

The need to establish whether there is a link between medical conditions and service in the Persian Gulf resulted in the initiation of a broad-based research program. The Working Plan for research is intended to help coordinate and focus the research efforts sponsored by the federal government in a coherent and cost-effective manner. This document presents an approach to answering questions about the nature of illnesses experienced by Persian Gulf veterans. This research is intended to pursue the following goals:

Establish the nature and prevalence of symptoms, diagnosable diseases, and other conditions in Persian Gulf veterans in comparison to appropriate control populations;

Identify possible risk factors for any excess morbidity or mortality among Persian Gulf veterans; and,

Identify appropriate diagnostic tools, treatment methods, and prevention/intervention strategies for conditions found among Persian Gulf veterans.

The research necessary to achieve these goals includes basic research, which is necessary to establish the knowledge base upon which clinical and epidemiological research are built. Where appropriate and feasible, research will address family members of veterans, as well as veterans per se.

2.3 RESEARCH MANAGEMENT AND COORDINATION

Research on Persian Gulf veterans’ illnesses is complex, involving a number of different approaches and outcomes. The federal research enterprise involves scientists conducting research sponsored by VA, DoD, and HHS. Each of these Departments have distinct, though complementary, capabilities and capacities for conducting and sponsoring research on Persian Gulf veterans health issues. Each Department has its own appropriation for extramural and intramural general biomedical research programs. Extramural funds generally support research efforts at non-federal institutions such as universities. Intramural funds generally support in-house research. However, at most VA medical centers, intramural research is conducted in conjunction with academic medical center affiliates. The Department of Defense also has a separate item in its appropriation for DoD/VA collaborative research on health problems shared by veterans and active duty service members alike.

The biomedical research programs in VA, DoD, and HHS have well established management structures for science policy formulation and the solicitation, scientific peer review, and funding of both extramural and intramural programs. The coordination and management of research on Persian Gulf veterans’ illnesses has required the establishment of an overall research policy framework linking each Department’s research management hierarchy. The linkage is provided through the Research Working Group of the Persian Gulf Veteran’s Coordinating Board [composed of representatives from VA, DoD, HHS, and the Environmental Protection Agency (EPA)]. The Research Working Group is charged with assessing the state and direction of research; identifying gaps in factual knowledge and conceptual understanding; identifying testable hypotheses; recommending research directions for participating agencies; reviewing research concepts as they are developed; collecting and disseminating scientifically peer-reviewed research information; insuring that the appropriate research is done without unnecessary duplication; and insuring that federally sponsored research undergoes appropriate peer review and oversight. As an operational policy, the Research Working Group works through the line management authority each department maintains over its intramural scientists, scientific program managers (responsible for extramural research), and their budgets.

Each Department engaged in research on Persian Gulf veterans’ illnesses emphasizes the need for ongoing prospective and retrospective peer review of research. Because of the urgency of the health concerns of Persian Gulf veterans and their families, as well as the diverse nature of the reported illnesses, review and oversight of research is essential. VA, DoD and HHS have established several oversight mechanisms to capture the diverse nature of the overall effort; some oversight mechanisms are broad-based, encompassing all research issues, whereas others are more focused on individual research projects and programs.

2.4 PURPOSE OF THE WORKING PLAN

This plan:

Identifies the knowledge needed to achieve the above-stated goals;

Identifies the knowledge that is currently available or will be obtained from ongoing research at some time in the foreseeable future;

Identifies the research areas that need to be covered to close the gap between what is known and what is needed.

This plan is a dynamic working document that will undergo periodic modifications as new knowledge emerges and as research findings improve the understanding of Persian Gulf veterans’ illnesses. The current document is the first revision of the original 1995 Working Plan and replaces the original document.

2.5 ORGANIZATION OF THIS DOCUMENT

To establish a knowledge baseline for the Working Plan, it is valuable to first examine the assessments of Persian Gulf veterans’ health issues carried out by various expert panels. These include the NIH Technology Assessment Conference on Persian Gulf Veterans Experience and Health, the National Academy of Science/Institute of Medicine/Medical Follow-Up Agency panel on the Health Consequences of Service During the Persian Gulf War, the Defense Science Board Task Force on Gulf War Health Effects, and the Presidential Advisory Committee on Gulf War Veterans’ Illnesses. Section 3 provides a brief overview of the assessments conducted by these panels. In the period since reports from the aforementioned panels were published there have been research findings that must be integrated with previous assessments. Section 4 is an assessment of research needs factoring in prior assessments, contemporary research findings, and the current research portfolio. Recommendations for additional research resulting from this assessment include research that is specific to the health experience of Persian Gulf veterans, as well as research that has long-term impact for future deployments and military conflicts.

The Persian Gulf Veterans’ Illnesses Research Database is provided for reference in the Appendix. To the best of our knowledge, it contains all relevant and credible research on Persian Gulf veterans’ illnesses sponsored by the federal government and, along with research information from the non-federal research sector, is the basis for the determination of future research directions. It also includes 15 new research projects awarded by DoD as a result of a Broad Agency Announcement (BAA) in 1995 soliciting research from federal and non-federal investigators. The selection of research projects was based on scientific merit and program relevancy. Program relevancy was determined in part by the research gaps identified in the 1995 Working Plan. A more detailed summary of federally sponsored research in 1995 can be found in the Annual Report to Congress: Federally Sponsored Research on Persian Gulf Veterans’ Illnesses, 1995 (PGVCB, 1996a)


3. GENERAL FINDINGS FROM PANEL ASSESSMENTS

In late 1993, as information from initial descriptive studies became available and plans for future studies were being developed, it was evident that an assessment of the data and investigational activities was in order. Assessment activities were undertaken by the Defense Science Board (DSB), the National Institutes of Health (NIH), the National Academy of Sciences/Institute of Medicine/Medical Follow-up Agency (IOM), and most recently by the Presidential Advisory Committee on Gulf War Veterans’ Illnesses.

3.1 DEFENSE SCIENCE BOARD

DoD commissioned the Defense Science Board Task Force on Gulf War Health Effects. The Task Force was specifically charged with reviewing all available intelligence and reports of detection of chemical agents and toxins during Operations Desert Shield/Desert Storm (ODS/DS) and the post-conflict period. In addition, the Task Force was to review scientific and medical evidence relating the possibility of low-level exposure to chemical and biological warfare (CBW) agents to potential long term health effects. A similar review was conducted for possible industrial pollutants and other potential causes of unexplained illnesses. The DSB Task Force met six times between November 1993, and March 1994. In the course of its work, the Task Force heard presentations from a wide range of scientific and medical experts from within and outside DoD. The Task Force published its final report in June 1994 (DSB, 1994). The members of the DSB Task Force reached consensus on a number of key points, including:

1. There is "... no scientific or medical evidence that either chemical or biological warfare was deployed at any level against us, nor that there were any exposures of US service members to chemical or biological warfare agents in Kuwait or Saudi Arabia."

2. There is "...no persuasive evidence that any of the proposed etiologies caused chronic illness on a significant scale in the absence of acute injury at initial exposure."

3. There is insufficient epidemiological evidence at this time "...to support the concept of any coherent ‘syndrome’."

Because many veterans report symptoms similar to Chronic Fatigue Syndrome (CFS), the DSB Task Force felt it would be advantageous to coordinate further research on veterans’ illness in this category with ongoing studies of CFS in the civilian population.

In light of new knowledge indicating there may have been release of chemical warfare agents in March, 1991 as a result of demolitions of weapons bunkers near Khamisiyah, Iraq (see Section 4.1.5), the first point is drawn into question. However, there is still no direct scientific or medical evidence of exposure.

3.2 NIH TECHNOLOGY ASSESSMENT WORKSHOP

The NIH Technology Assessment Workshop, "Persian Gulf Experience and Health", was convened April 27-29, 1994, and was co-sponsored by VA, DoD, HHS, and the Environmental Protection Agency (EPA). The expert panel addressed four issues: (1) the prevalence of unexplained illnesses; (2) whether a case definition could be developed; (3) potential etiologies of unexplained illnesses; and (4) recommendations for future research.

The NIH panel found that insufficient epidemiological data existed to determine whether there was an increased prevalence of illnesses among veterans due to service in the Persian Gulf War (NIH, 1994). The panel also concluded that while there are several complexes or patterns of symptoms unexplained by established disease categories, it would be premature to establish a case definition. The panel could not identify a single or multiple etiology for unexplained illnesses, but noted the appearance in some Persian Gulf veterans of a newly identified form of leishmaniasis (viscerotropic leishmaniasis). The panel also suggested that the unique stresses of the Persian Gulf experience may have led to a previously unrecognized manifestation of post-traumatic stress disorder (PTSD).

3.3 NATIONAL ACADEMY OF SCIENCES/INSTITUTE OF MEDICINE/ MEDICAL FOLLOW-UP AGENCY

As directed by P.L. 102-585, VA and DoD entered into a contract with the National Academy of Sciences/Institute of Medicine/Medical Follow-up Agency (IOM) to "...review existing scientific, medical, and other information on the health consequences of military service in the Persian Gulf theater of operations during the Persian Gulf War." In contrast to the NIH Workshop, this effort was designed to conduct an assessment in greater depth, over a three year time period.

On January 4, 1995, the IOM issued a report "Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Action" (IOM, 1995). In general the IOM panel endorsed the DSB and NIH findings of no single disease entity with no single etiology. The panel also strongly emphasized the importance of population-based studies. The panel found no evidence that either chemical or biological warfare (CBW) agents were used against coalition troops during the Persian Gulf conflict and, as a consequence, recommended that this not be a factor in considerations of the causes of Persian Gulf veterans’ illnesses.

The IOM panel completed its deliberations in the Summer of 1996 and issued its final report in September, 1996 (IOM, 1996). In this report (which stands as a separate document from the January, 1995 report) the panel stated that it could find no scientific evidence to date demonstrating adverse health consequences associated with service in the Persian Gulf War beyond the few documented cases of leishmaniasis, combat-related or injury-related mortality or morbidity, and increased risk of psychiatric sequelae of deployment. The panel went on to state that there is a strong likelihood that no single hypothesis could account for all of these, whether or not the illnesses result from service in the Persian Gulf War. Finally, the panel observed that after previous wars and conflicts, a proportion of military service personnel and veterans have had medical complaints of varying degrees of severity that are not explainable based on identifiable health hazards or physical illnesses. This observation echoes work by Hyams et al (1996) tracing such a phenomenon back at least to the Civil War.

3.4 PRESIDENTIAL ADVISORY COMMITTEE ON GULF WAR VETERANS’ ILLNESSES (PAC)

The President established this advisory committee by Executive Order on May 26, 1995. The 12 member committee is composed of scientists, health care professionals, veterans, and policy experts. The Committee is charged with reviewing and providing recommendations on the full range of government activities relating to Persian Gulf veterans’ illnesses.

The Committee released an interim report in February 1996 (PAC, 1996a). Although the Interim Report stated that VA, DoD, and HHS research programs are generally well designed and should lead to answers, it also had several recommendations. The Committee’s recommendations covered issues such as peer review, coordination of agency research activities, the use of public advisory committees and the availability of information on troop exposure. In response to the Interim Report, the agencies developed a coordinated plan of action (PGVCB, 1996b) that responds to the Advisory Committee’s interim recommendations. The final report of the Committee is scheduled for release in December, 1996.

The Committee made no findings about specific illnesses or exposures in the Interim Report. However, at a public meeting of the PAC in Chicago, Illinois, on July 8-9, 1996 (PAC, 1996b), Committee Staff presented to the Committee their assessment of major potential risk factors. A meeting in Cincinnati, Ohio, on July 23, 1996 (PAC, 1996c) was devoted specifically to stress as a risk factor, and a meeting in Denver, Colorado, on August 6, 1996 (PAC, 1996d) revisited depleted uranium and oil well fires as risk factors. As in the IOM Final Report (IOM, 1996), Committee Staff were unable to identify any single risk factor, other than stress, that could explain a large number of illnesses reported by Persian Gulf veterans. It should be emphasized that these conclusions were those of Committee Staff and do not necessarily represent the final findings of the Committee proper.

As will be seen from the discussion of various exposures and health outcomes in the next section, the views of the Persian Gulf Veterans Coordinating Board Research Working Group do not diverge from those of the various review and assessment panels. As new information has become available, however, we continue to build on these reviews and assessments. Nevertheless, the door must not be closed to considerations of other exposures and outcomes since new research findings from ongoing studies have the potential for affecting these conclusions.


4. FRAMING THE PROBLEM

In the 1995 Working Plan a set of research questions were developed based on the NIH, DSB, and IOM (in the initial report of January, 1995) findings and recommendations. Each question was followed by an evaluation of the degree to which then current research was addressing these questions, followed by a set of recommendations for additional research. In this revised version the formulation of these questions is restated. Current, on-going (or recently completed) research projects addressing these questions are then presented along with relevant findings. This is followed by an updated list of research needs for the question of concern.

As with the 1995 Working Plan, the most important question about the health of Persian Gulf veterans is:

Are Persian Gulf veterans experiencing a greater prevalence of symptoms and illnesses in comparison with an appropriate control population?

From the answer to this question springs virtually all subsequent questions that may be addressed through research. For example, if there is an increased prevalence of certain symptoms among Persian Gulf veterans in comparison to controls, then what disease or diseases are being manifested by these symptoms, and what connection with service in the Persian Gulf might exist? Therefore, the first research question that needs addressing is:

RESEARCH QUESTION 1
What is the prevalence of symptoms/illnesses in the Persian Gulf veterans population? How does this prevalence compare to that in an appropriate control group?

In the past year two studies (CDC, 1995; Kaiser et al, 1995) have demonstrated that while objective measures remained consistent between study and comparison groups, in select cohorts of Persian Gulf veterans there is a greater prevalence of symptoms (similar in type to the VA Persian Gulf Registry and the DoD CCEP) when compared to non-deployed veterans. Because of the limited sizes of these cohorts generalizability is difficult. In addition, Coate et al (1995) have shown that active duty service members who served in the Persian Gulf had no more hospital admissions than those who were not deployed to the Persian Gulf. This suggests that as a group Persian Gulf veterans are not experiencing a greater prevalence of major illnesses.

Research Underway

PROJECTS VA-2, 4, 5, 6, 18; DoD-1A,B,E,F, 30, 39; HHS-1, 2 (NOTE: Project numbers associated with current research refer to projects contained in the Appendix.): Components of each of these projects are designed to estimate the prevalence of symptoms in Persian Gulf veterans and compare this prevalence to control groups of non-deployed veterans.

Additional Research Needed

The ongoing epidemiological studies will determine the need for additional studies.

If ongoing studies continue to demonstrate an increased prevalence of self-reported symptoms and illnesses, then the secondary questions regarding disease entity or entities must continue to be vigorously pursued.

Casting the problem of Persian Gulf veterans’ illnesses into an exposure-outcome framework helps to isolate two interconnected questions: (1) what was the nature and extent of possible exposures experienced by veterans while in the Persian Gulf?, and (2) what adverse health outcomes, if any, have occurred among Persian Gulf veterans, beyond what would be normally expected in such a large population? These two questions lead to a third, namely:

(3) is there a relationship, or set of relationships, between exposure to the complex environment of the Persian Gulf War theater and any excess health outcomes that is consistent with established biological and toxicological principles, and with epidemiological data? This last question requires identification and quantitation of both exposures and health outcomes. Investigation of exposures can lead to hypotheses about expected health outcomes based on the nature and extent of the exposures, and investigations of health outcomes can lead to hypotheses about exposures.

Because of the inherent logical value of separating the problem into exposure and health outcome, the Working Plan separates research oriented primarily toward exposure from research directed primarily at evaluating health outcomes.

4.1 EXPOSURES

While deployed in the Persian Gulf theater, troops may have experienced a variety of exposures, both natural and environmental/occupational in origin, to a varied extent. Potential exposures of concern that have been cited are: infectious agents (such as Leishmania tropica); smoke from oil well fires; exposure to other petroleum products and their combustion products; other occupational exposures such as pesticides, chemical agents resistant coating (CARC) paint; CBW agents; vaccines; pyridostigmine bromide (PB); and psychophysiological stressors of war. The number of troops and the amount of exposure to any one, or combination of, these exposures is not known at this time.

TABLE 2

Summary of Potential Exposures of Concern for Health Outcomes

Exposures

Scientific Review Panel

DSB NIH IOM

Infectious Agents

+

+

+

Smoke from Oil Well Fires/Oil Spills

-

-

-

Other Petroleum
Products

*

+

+

Other Occupational
Exposures

*

+

*

CBW Agents

-

*

-

Vaccines

-

-

+

Pyridostigmine

*

+

+

War Stressors

+

+

+

 

+ Recommended for further review and research

- Unlikely to be of primary concern for long-term health consequences

* The exposure was either considered by the panel, but not highlighted, or was not considered by the panel.

Table 2 summarizes the findings of the DSB, NIH, and IOM panels with respect to these exposures. All three panels agreed that psychophysiological stressors of war and infectious agents required further review or research. Further research into exposure to other petroleum products and pyridostigmine bromide was recommended by IOM and NIH, but DSB made no specific recommendation. All three panels also agreed that it is unlikely that oil well fires or vaccines caused illnesses in Persian Gulf veterans.

With respect to CBW exposure, the NIH panel initially deferred making a finding about CBW until the DSB completed its deliberations. Both the DSB and the IOM (in its January, 1995 initial report) subsequently reported lack of confirmation of exposure to CBW agents. Further research related to these potential exposures was not recommended by DSB or IOM in its initial report (IOM, 1995). Recent findings that exposure of US service members to chemical warfare agents may have occurred near Khamisiyah, Iraq in March, 1991 have significantly altered this view (see Section 4.1.5 below).

Below is a discussion of each of the exposures. For each exposure a general background is provided along with any new research data that have become available. This is followed by specific research questions with statements of current research and any additional studies that are needed. Studies that pace other studies (i.e., studies that must be complete before others can proceed) or studies that are paced by other studies are identified.

 

4.1.1 Infectious Agents

Coalition troops were exposed to a number of infectious agents present in the Persian Gulf area. The most notable of these is the parasite Leishmania tropica. To date only 12 cases of viscerotropic and 20 cases of cutaneous leishmaniasis have been diagnosed among Persian Gulf veterans (DoD, 1996), clearly suggesting minimal exposure. Diagnosis of viscerotropic leishmaniasis, however, is difficult because there is no accurate serological test for the presence of the parasite. Thus, actual exposure and infection rates are difficult to obtain. After the passage of five years and the absence of a significant number of cases of either cutaneous or viscerotropic leishmaniasis, the likelihood of L. tropica as an important risk factor for widely reported illnesses has diminished.

Other infectious agents were also present in the Persian Gulf area that could cause chronic diseases, including schistosomiasis, Q fever and brucellosis (DeFraites et al, 1992; Ferrante MA et al, 1993). Only a few cases of these diseases have been diagnosed among the US troops who served in the Persian Gulf, and there is no indication that such infections are widespread or are related to unexplained illnesses (Hyams et al, 1995).

Acute infectious disease outcomes typical of cramped military living conditions, such as dysentery and respiratory tract infection, were actually lower than expected during the Persian Gulf conflict (DSB, 1994; Richards et al, 1993a,b; Richards et al, 1991). Exposure to other infectious agents such as mycoplasmas, bacteria, viruses, and fungi probably occurred but there is not a strong case from any clinical evaluations that supports these organisms as possible etiologic factors. However, because of the possible role for Leishmania in unexplained illnesses, all three scientific review panels recommended further research to develop a simple, sensitive and specific diagnostic test.

RESEARCH QUESTION 2
What was the overall exposure of troops to Leishmania tropica?

If this question is to be ultimately addressed, a highly sensitive, yet specific diagnostic screening test must be developed. Only then would it be possible to address the research question. Progress has been reported by Dillon et al (1994) who have developed a recombinant antigen that has been characterized and detects immune response in patients with viscerotropic leishmaniasis. Specificity and sensitivity of this test are currently unknown. Because of the potential for development of specific and sensitive serological tests, serum samples collected as a part of population-based epidemiological studies of Persian Gulf veterans should be banked, when feasible and practical, to facilitate testing once an appropriate test is available.

Despite the diminishing likelihood of L. tropica as a risk factor, it is worthwhile to continue work in this area because it is relevant for future deployments.

Research Underway

PROJECT DoD-8A,B, 38: These three projects involve development of a reliable skin test (screening for past infection) and serologic assay (testing for active infections).

Additional Research Needed

Development and testing of diagnostic tests determine all further leishmaniasis research directed at this research question.

4.1.2 Smoke from Oil Well Fires and Oil Spills

The US Army Environmental Hygiene Agency has characterized the carcinogenic and non-carcinogenic risk from exposure to smoke from the Kuwait oil well fires (USAEHA, 1994). This risk assessment demonstrates minimal potential carcinogenic risk. The bulk of non-cancer risk is from volatile organic compounds, but this risk is judged to be low. These risk assessments, however, are only valid for personnel located at sites where environmental measurements were made. In DoD-18 an oil well plume model is being developed using monitoring data as input. The model output, when expressed in a format compatible with the military geographic information system (GIS) for troop unit location (PROJECT VA-3), should provide an approximation of the oil well plume exposure as a function of time for troop units. This model will prove to be very valuable for future spatial analyses requiring exposure information. DoD and VA need to ensure that this model has been adequately peer reviewed. Based on previous recommendations of review panels and the lack of any new information that alters the findings, further oil well smoke exposure research beyond the USAEHA model, and its application to risk assessment, is not being pursued at this time.

4.1.3 Other Petroleum Products

During the war, some troops may have been exposed to petroleum vapors, solvents and combustion products. Kerosene, diesel and leaded gasoline from local sources were sometimes used for heating, ground spraying to suppress sand dust, and incinerating both trash and human waste. As a result, some troops could have been exposed to benzene, toluene, ethylbenzene, xylene and other petroleum combustion products. Elevated levels of sulfur dioxide, nitrogen dioxide, nitric acid, acidic sulfates, carbon monoxide, lead, respirable particulates and other pollutants may be expected in tents using unvented heaters burning gasoline and diesel fuels. There were no measurements of any of these pollutants in tents. Concern that this type of exposure was high enough for significant health consequences prompted both the NIH and IOM panels to recommend a simulation of exposure in tents heated by diesel fuel with composition similar to that used in the Persian Gulf area. The IOM noted the presence of elevated blood lead levels derived from autopsy specimens from seven service members who died in the Persian Gulf theater may have been related to contamination from specimen storage containers (IOM, 1996). The pharmacokinetics of lead make meaningful follow-up difficult at best (Legett RW, 1993). In an ongoing clinical study, investigators have not found any evidence of current elevated blood lead levels among Persian Gulf veterans (Roswell, 1995).

RESEARCH QUESTION 3
What were the exposure concentrations to various petroleum products, and their combustion products, in typical usage during the Persian Gulf conflict?

In one attempt to address this question investigators at NIH (HHS-3), in conjunction with USAEHA, have measured urinary metabolites of polycyclic aromatic hydrocarbons (PAH), PAH-DNA adducts, and genetic polymorphisms in 62 soldiers in June 1991, prior to deployment to Kuwait, eight weeks into their deployment, and after their return to Germany from Kuwait in October 1991. Results indicate that soldiers may not have experienced significant exposures to PAHs associated with the incomplete combustion of petroleum while stationed in Kuwait.

Research Underway

PROJECT DoD-2, 34: A component of DoD-2 involves the simulation of exposures to petroleum and petroleum combustion products in enclosed spaces. DoD-34 involves direct simulations of exposures in tents characterizing the nature and concentrations of petroleum combustion products.

PROJECT DoD-19: This research attempts to expand the modeling of DoD-18 to characterize all potential exposures in Kuwait and Saudi Arabia.

Additional Research Needed

DoD and VA need to ensure that this and other exposure models have been adequately peer reviewed.

4.1.4 Other Occupational Exposures

Other potential environmental hazards, including pesticides, microwaves, chemical agent resistant coating (CARC) paint fumes, depleted uranium (DU) and cleaning solvents were present in the Persian Gulf theater. Some of these chemicals, such as CARC paint and DU, are not likely to be a primary cause of unexplained illnesses among Persian Gulf veterans because only small numbers of troops were exposed (NIH, 1994). A full assessment of risk from exposure to these chemicals cannot be made in the absence of accurate exposure data.

RESEARCH QUESTION 4
What was the extent of exposure to specific occupational/environmental hazards known to be common in the Persian Gulf veteran’s experience? Was this exposure different from that of an appropriate control group?

Research Underway

PROJECT DoD-2: In addition to the petroleum and combustion products simulations listed above, simulations of exposure to other chemicals will also be conducted.

PROJECT DoD-19: This research attempts to expand the risk assessment modeling of DoD-18 to characterize all potential exposures in Kuwait and Saudi Arabia.

PROJECTS VA-2, 4A, 5A, 6-Core, 13; DoD-1A,D,E, 30, 39; HHS-1,2: Components of each of these epidemiology studies will collect self-reported exposure data using a variety of survey instruments. Results of exposure simulations may help to estimate the level of self-reported exposures.

Additional Research Needed

The ongoing studies will determine the need for additional studies.

4.1.5 Chemical and Biological Warfare Agents

Both the DSB and IOM panels concluded that reports of the possible use of CBW agents cannot be confirmed and that bombing of Iraqi storage areas did not cause CBW agent exposure. While awaiting assessment of the DSB, the NIH panel drew no conclusions about the presence or absence of CBW. The IOM panel in their initial report (IOM, 1995) stated that claims of exposure to chemical or biological warfare agents should not be made or given credence in the absence of reliable substantiating data. Despite this, the DoD established the Persian Gulf Investigations Team (PGIT) to investigate, among other things, reports of CBW exposure provided to a 1-800 hotline.

In June 1996, DoD announced that a munitions bunker (#73) in Khamisiyah, Iraq, destroyed by US demolition teams on March 4, 1991, probably contained the chemical agents sarin and cyclosarin. On March 10 a pit containing sarin was also destroyed by US troops. Because of this, it is likely that some US military personnel in the vicinity were exposed to chemical warfare agents. In addition, chemical weapons storage sites at Muhammadiyat, and Al Muthanna, Iraq (northwest of Baghdad), were destroyed by allied bombing at the beginning of the Persian Gulf War, creating a potential risk of chemical agent exposure downwind of these sites.

Testimony provided to the Presidential Advisory Committee meeting on June 8-9, 1996, (PAC, 1996b) by representatives of the United Nations Commission charged with the accounting and destruction of weapons of mass destruction in Iraq, and by the US Central Intelligence Agency (CIA), suggest that Khamisiyah was the only site in southern Iraq and Kuwait at which chemical weapons were present. If this is so, the incident at Khamisiyah may be entirely isolated. However, the report itself raises a sufficient degree of uncertainty to conclude that potential exposures to chemical warfare agents should no longer be excluded from consideration as a valid subject of research .

Two exposure issues immediately arise. The first one relates to the potential exposure of troops present at the Khamisiyah site at the time of demolition, and the potential exposure of troops as a result of the bombing of the Muhammadiyat and Al Muthanna weapons depots. The second relates to the more general issue of chemical agent exposure.

RESEARCH QUESTION 5
What were the potential exposures of troops to organophosphate nerve agent and/or sulfur mustard as a result of allied bombing at Muhammadiyat and Al Muthanna, or the demolition of a weapons bunker at Khamisiyah

In testimony at the June 8-9, 1996, PAC meeting (PAC, 1996b), contractors to the CIA presented the results of model calculations predicting ground level concentration of chemical agent as a function of distance and direction away from the March 4 detonation site at Khamisiyah (CIA, 1996). The model predicts that at the location of the troops chemical agent concentration should have been below any level expected to produce even mild acute effects. The CIA also modeled the plumes resulting from the bombings at Muhammadiyat and Al Muthanna. The model predicts levels well below what would be expected to cause even mild acute effects for troops located 400 - 500 km south of the sites. At the time of this writing, CIA has not completed its model calculations for ground level sarin concentrations resulting from the March 10 pit detonation. At the moment, model predictions provide some reassurance. However, model applications to these situations need to undergo scrutiny by outside experts.

Many of the ongoing epidemiological investigations collect self-reports on chemical agent exposure. Although these data may have value in assessing risk factors, the potential for report bias is always present. In the absence of actual exposure data acquired at the site of detonation, only model calculations can presently be relied upon. Exposure biomarkers for chemical agents have the potential for determining exposure on an individual basis after an actual exposure has ceased. However, there are no known exposure biomarkers for either organophosphate nerve agents or vesicants, and even if there were they would probably be of little value since over five years have elapsed since the Persian Gulf War.

Research Underway

PROJECTS VA-2, 4A, 5A, 6-Core, 13; DoD-1A,D,E, 30, 39; HHS-1,2: Components of each of these epidemiology studies are collecting self-reported exposure data using a variety of survey instruments. Although these studies are not directly focused on troops present at Khamisiyah, self-reporting and input from the troop unit locator database may provide some information on potential exposure, albeit not necessarily more detailed than time and location of individual units. Results of further exposure simulations may help to estimate the intensity of self-reported exposures.

Additional Research Needed

Existing plume model calculations should be critically reviewed.

Exploration of the development of practical, sensitive, and specific biomarkers of exposure to chemical agents including organophosphate nerve agents and vesicants such as sulfur mustard.

The second exposure question can be stated as:

RESEARCH QUESTION 6
What was the extent of exposure to chemical agent, other than at Khamisiyah, Iraq, in the Persian Gulf as a function of space and time?

Despite the evidence indicating the very low probability of widespread chemical warfare agent exposures in the Persian Gulf, concern has been elevated by the bombings of Muhammadiyat and Al Muthanna, and the event at Khamisiyah in March 1991. Consequently there is a need to evaluate the potential for exposure of troops to chemical agent at other times and locations. In the absence of quantitative data, virtually all exposure information will be derived from self-reports, and thus, subject to bias. Although exposure biomarkers are probably of little use in the context of any chemical warfare agent exposure in the Persian Gulf, the need for reliable objective exposure markers is evident.

Research Underway

PROJECTS VA-2, 4A, 5A, 6-Core, 13; DoD-1A,D,E, 30, 39; HHS-1,2: Components of each of these epidemiology studies are collecting self-reported exposure data using a variety of survey instruments.

Additional Research Needed

Exploration of the development of practical, sensitive, and specific biomarkers of exposure to chemical agents, including organophosphate nerve agents and vesicants such as sulfur mustard.

With respect to biological warfare agents, there continues to be no evidence of use by Iraq, or exposure of troops during or after the Persian Gulf War. These determinations were confirmed by both UN and CIA officials at the July 1996 meeting of the PAC (PAC, 1996b). The absence of any reports of infection from anthrax or acute illnesses from botulinum toxin in the Persian Gulf theater lends further credence to this conclusion.

4.1.6 Vaccines

Troops who served in the Persian Gulf conflict were vaccinated without significant side-effects against common infectious diseases with vaccines frequently used in the general population. In addition, approximately 150,000 troops received at least one dose of anthrax vaccine and about 8,000 received at least one dose of botulinum toxoid. Both vaccines have been used for many years without adverse effects. All three review panels stated that no long-term adverse effects have been documented or would be expected. Further study of the potential adverse effects of vaccines in this population is not recommended by any of the three panels, nor is it endorsed in this plan.

4.1.7 Pyridostigmine Bromide

Pyridostigmine bromide (PB) is a cholinesterase (ChE) inhibitor that was supplied to troops for use as prophylaxis against exposure to nerve agents. PB was distributed to troops in blister packs of 21 tablets of 30 mg each. PB tablets were taken on order when it was believed a gas attack was imminent. The recommended dosage was one tablet every 8 hours. PB has been in use for decades (at much higher dosages) in the treatment of patients with myasthenia gravis. Short-term side effects are well known -- e.g., nausea, vomiting, diarrhea, abdominal cramps, increased salivation, miosis, headache and dizziness. There have been no documented long-term side effects of this drug. Exposure information is provided solely from self-report of veterans.

RESEARCH QUESTION 7
What was the prevalence of PB use among Persian Gulf troops?

Research Underway

PROJECTS VA-2, 4A, 5A, 6-Core; DoD-1A,D,E, 30, 39; HHS-1,2: Components of each of these epidemiological studies collects self-reported PB use data for Persian Gulf veterans using a variety of instruments.

Additional Research Needed

The ongoing epidemiological studies will determine the need for additional studies.

4.1.8 Psychophysiological Stressors of War

Psychiatric morbidity among US troops deployed to the Persian Gulf area was predicted even though the war was of short duration, resulted in relatively low numbers of casualties, and positive support for the war prevailed at home. Persian Gulf veterans were exposed to many psychophysiological stressors besides direct combat, such as sudden mobilization for military service (especially among members of reserve and National Guard units), exposure to dramatic oil well fires, the constant threat of CBW agents, and fear of combat in general. A wide range of somatic and psychological responses could be expected from individuals deployed to the Persian Gulf area from stress associated with deployment (Wolfe et al, 1993; Ursano and Norwood, 1996). All three review panels recognized the possible role of psychophysiological stressors associated with deployment and the possibility of a psychophysiological response among Persian Gulf veterans. All three panels, and the Committee Staff of the PAC (PAC, 1996d), have encouraged further scientific research in this area.

RESEARCH QUESTION 8
What was the prevalence of various psychophysiological stressors among Persian Gulf veterans? Is the prevalence different from that of an appropriate comparison population?

Research Underway

PROJECTS VA-2, 4A, 5A, 6-Core, 7, 12; DoD-1A,D,E, 4, 5, 6A,B, 30, 39, 40; HHS-1, 2: Components of these studies are acquiring self-reported data on exposure to psychophysiological stressors among Persian Gulf veterans and appropriate control populations. DoD-30 and DoD-39 will add specific information about the stressors in female Persian Gulf veterans and in British Persian Gulf veterans respectively.

Additional Research Needed

More research is needed on the role of a variety of stressors as risk factors for later development of stress-related disorders, including, but not limited to, PTSD.

4.1.9 Troop Locations

One of the most important variables in considering any exposure is determining the location in the Persian Gulf War theater of individual service members as a function of time. Information about troop location down to the individual service member was not recorded. However, unit diaries (where a unit consists of approximately 100 troops) were maintained on a daily basis for all units. Matches between units and individuals can be made. The US Army and Joint Services Environmental Support Staff Group (ESG) is currently in the process of computerizing troop unit locations (PROJECT VA-3). Computerized records were completed for the Air Force, Navy, and Marines at the end of 1995. Eighty percent of the records were completed for the Army at the end of 1995. The remaining records will be complete by late 1996. Because the results from this project are needed for several epidemiological investigations, this project is of vital importance.

4.2 HEALTH OUTCOMES

The most frequently cited health outcomes and concerns related to service in the Persian Gulf are:

Non-specific symptoms/symptom complexes;

Immune function abnormality/autoimmune disease;

Reproductive health outcomes;

Genitourinary disorders;

Pulmonary function abnormality;

Neuropsychological/neurological outcomes;

Psychological/psychiatric outcomes;

Infection;

Cancer/neoplastic disease;

Mortality outcomes.

Table 3 provides a summary of the DSB, NIH, and IOM findings on health outcomes. When the potential for long-term health consequences was considered, all panels agreed that further research into psychological outcomes, non-specific symptom complexes, and leishmaniasis was needed. In addition, the IOM and NIH panels recommended research on neurological and neuropsychological outcomes. The remaining potential health outcomes were each considered significant by only one panel. In such cases, though, the other two panels had no comment. This latter observation must be treated with caution since concern about some potential health outcomes have been raised only recently.

TABLE 3

Summary of Reported Health Outcomes

Health Outcomes

Scientific Review Panels

DSB NIH IOM

Non-specific Symptoms/ Symptom Complexes**

+

+

+

Immune Function Abnormality

*

*

*

Reproductive Health Outcomes

*

*

+

Genitourinary Disorders

*

*

+

Pulmonary Function

Abnormality

*

+

*

Neuropsychological - Neurological Outcomes

*

+

+

Psychological/psychiatric

Outcomes

+

+

+

Infection

+

+

+

Cancer/Neoplastic Disease

*

*

*

Mortality Outcomes

*

*

+

+ Recommended for further review and research

- Unlikely to be of primary concern for long-term health consequences

* The outcome was either considered by the panel, but not highlighted, or was not considered by the panel.

** Including Chronic Fatigue Syndrome (CFS), chemical sensitivities, and fibromyalgia

Below, each health outcome is considered individually. For each health outcome a general background is provided. This is followed by specific research questions with statements of current research and any additional studies that are needed.

4.2.1 Non-Specific Symptoms/Symptom Complexes

Within any population the size of the Persian Gulf veterans cohort (approximately 700,000 who served in Operations Desert Shield/Desert Storm), individuals will experience various health complaints and may become ill at some time. Some of these symptoms and illnesses may not be fully explained despite intensive clinical work-ups. On the other hand, it is possible that some of these symptoms may fall into unique complexes that can be categorized.

RESEARCH QUESTION 9
Are Persian Gulf veterans more likely than an appropriate comparison group to experience non-specific symptoms and symptom complexes?

Recently, investigators have demonstrated in 1498 Seabees (Construction Battalion personnel) an increase of symptoms among deployed versus non-deployed Seabees with no physical correlates (Kaiser et al, 1995). Investigators with the CDC and the State of Pennsylvania have also demonstrated an increase of symptoms within groups of deployed versus non-deployed Air National Guardsmen in Pennsylvania (CDC, 1995). Symptom patterns in the latter study bear a similarity to Chronic Fatigue Syndrome, however the severity of symptoms is milder than in Chronic Fatigue Syndrome.

Research Underway

PROJECTS VA-2, 4A, 5A, 6-Core, 18; DoD-1A,E, 30, 39, 40; HHS-1,2: Components of each of these studies are acquiring data on self-reported non-specific symptoms. Some (see below) are also investigating the presence of identifiable symptom complexes. DoD-30 and DoD-39 are collecting data in cohorts of women and British Persian Gulf veterans respectively. DoD-40 is not designed to address prevalence of illness, but is a longitudinal study of PTSD in Persian Gulf veterans.

PROJECT VA-2; HHS-2: These studies include a physical examination to validate the self-reported symptoms on a subset of the survey study population.

PROJECTS VA-4A, 4B, 5B, 5C, 6B; DoD-31, 32, 39; HHS-2: Components of these studies are directed specifically at hypotheses that unexplained illnesses are associated with symptom complexes identified as CFS, fibromyalgia, or other symptom-based syndromes. At a minimum they should provide information on the prevalence of these complexes.

Additional Research Needed

Most of the ongoing epidemiological studies are cross-sectional in nature. There needs to be additional emphasis placed on longitudinal studies focusing on the health of Persian Gulf veterans.

4.2.2 Immune Function

Suggestions have been made that some Persian Gulf veterans have experienced an alteration in immune function or host defense. One hypothesis is that aromatic hydrocarbons, and other related compounds, may cause suppression of immune function through activation of the aromatic hydrocarbon receptor (AhR) on cell lymphocytes and, subsequently, induction of lymphocyte death, thereby suppressing immune function.

RESEARCH QUESTION 10
Do Persian Gulf veterans have a greater prevalence of altered immune function or host defense when compared with an appropriate control group?

Research Underway

PROJECTS VA-4A, 5A, 6-Core, 17; DoD-37, 48: Virtually all of these studies are collecting standard, clinical immune function data. VA-4A is conducting research on a model for the upregulation of the AhR. VA-5A is studying peripheral blood polymorphonuclear leukocytes for chemokine expression. VA-5A is also examining blood mononuclear cells for reactivation for EBV, CMV, herpes 6 and herpes 7. DoD-37 is investigating alterations of immune response in male and female rats following PB, DEET, and permethrin exposures, alone or in combination. This project is also conducting in-vitro investigations of the effects of exposure to these compounds on human lymphocyte immune response. DoD-48 is investigaing the frequency of chromosome 7 inversions in blood specimens of symptomatic and asymptomatic Persian Gulf veterans.

Additional Needed Studies

The ongoing studies will determine the need for additional studies.

4.2.3 Reproductive Health Outcomes

Adverse pregnancy and birth outcomes associated with Persian Gulf area deployment have been a major concern among the Persian Gulf veterans. The IOM panel has recommended that reproductive outcomes be included among the health endpoints in surveillance programs and that population-based studies of these outcomes be conducted.

RESEARCH QUESTION 11
Is there a greater prevalence of birth defects in the offspring of Persian Gulf veterans than in an appropriate control population?

An investigation was conducted by the Mississippi Department of Health in collaboration with CDC of birth defects in children of Persian Gulf veterans from a Mississippi national guard unit (Penman, 1996). Birth defects were identified and the diagnoses verified. The results were compared to expected values. The number of birth defects was not higher than expected for that population although the study had inadequate statistical power to detect any differences in specific defects. Investigators at the Naval Health Research Center in San Diego have examined military hospital discharge records for births to spouses of deployed active duty service members and among deployed active duty women (Cowan et al, 1995). They found that when these women were compared to their non-deployed counterparts, no difference in birth defects between the two groups could be found. Data have been collected to determine the prevalence of Goldenhar Syndrome among infants of the same populations (Araneta, 1996).

Current Research

PROJECTS VA-2, DoD-1D,E, 30; HHS-1: Components of each of these epidemiological studies are identifying through survey questionnaires birth defects in offspring of Persian Gulf veterans and in those of appropriate controls.

PROJECT DoD-1G: This study will match Persian Gulf veterans and non-deployed era veterans with birth defects registries in 7 states to determine if the overall and diagnostic-specific prevalence of congenital abnormalities differs among Persian Gulf veterans, non-deployed era veterans and the general population.

PROJECT DoD-35: This is a feasibility study to determine if all children born to Persian Gulf veterans residing in California can be identified and if congenital anomalies in the first year of life can be identified.

Additional Research Needed

The ongoing epidemiological studies will determine the need for future studies.
RESEARCH QUESTION 12
Have Persian Gulf veterans experienced lower reproductive success than an appropriate control population?

Research Underway

PROJECTS VA-2; DoD-1D,E,C, 30; HHS-1: Different components of each of these studies will investigate the prevalence of failure to conceive, miscarriage, spontaneous abortion, and stillbirth and compare the prevalence to that of an appropriate control population.

Additional Research Needed

The ongoing epidemiological studies will determine the need for future studies.

4.2.4 Genitourinary Disorders

There have been individual reports of sexual dysfunction among Persian Gulf veterans, including infrequent reports of these phenomena in both the VA and DoD surveillance systems.

RESEARCH QUESTION 13
Is the prevalence of sexual dysfunction greater among Persian Gulf veterans than among an appropriate comparison population?

Research Underway

PROJECTS VA-2; DoD-1A, 1E, 30, 39; HHS-1: Components of these epidemiology studies will determine, through survey questionnaires, the prevalence of various manifestations of sexual dysfunction in Persian Gulf veterans (or in the veterans’ partners) compared to that in an appropriate comparison population.

PROJECT DoD-44: This project will investigate immunologic mechanisms by which a women could develop an allergic reaction to her sexual partner’s semen.

Additional Research Needed

The ongoing epidemiological studies will determine the need for additional studies.

4.2.5 Pulmonary Function Abnormality

Some troops may have been exposed to potentially significant amounts of petroleum vapors, combustion products and sand dust. Depending on exposure concentration and absorbed dose, repeated and chronic exposure to these chemicals and substances could possibly result in impairment of pulmonary function. The NIH panel recommended a retrospective cohort study to investigate pulmonary function related to petroleum combustion products.

RESEARCH QUESTION 14
Do Persian Gulf veterans report more pulmonary symptoms or diagnoses than persons in appropriate control populations?

DoD investigators have found that while active duty deployed Persian Gulf veterans from a Seabee unit self-reported more respiratory symptoms, their objective pulmonary function tests did not differ from a non-deployed control group (Kaiser et al, 1995).

Research Underway

PROJECTS VA-2, 4A, 5A, 6-Core; DoD-1A, 1E, 30, 39; HHS-1: Components of these studies are using surveys to ascertain the self-reported prevalence of pulmonary symptoms/diagnoses (e.g., asthma, bronchitis, etc.) among Persian Gulf veterans compared to an appropriate control population. Exposure-outcome relationships will be explored.

Additional Research Needed

The ongoing epidemiological and other studies will determine what, if any, additional studies are required.

RESEARCH QUESTION 15
Do Persian Gulf veterans have a smaller baseline lung function in comparison to an appropriate control group? Do Persian Gulf veterans have a greater degree of non-specific airway reactivity in comparison to an appropriate control group?

Research Underway

PROJECTS VA-4D; DoD-1A, 39: These projects are conducting cohort studies to determine whether there are any differences in pulmonary function and, to a lesser extent, airways reactivity between Persian Gulf veterans and Persian Gulf era veterans. As mentioned previously, DoD investigators have found that although active duty deployed Persian Gulf veterans from a Seabee unit self-reported more respiratory symptoms, their objective pulmonary function tests did not differ from a non-deployed control group (Kaiser et al, 1995).

PROJECTS DoD-2, 3: Components of these projects involve exposures of laboratory animals to a variety of inhaled pollutants. Pathophysiologic effects that may provide information on potential human health outcomes will be studied.

Additional Research Needed

The ongoing studies will determine the need for additional studies.

4.2.6 Neuropsychological and Neurological Outcomes

The subjective reports of generalized fatigue and cognitive impairment in Persian Gulf veterans enrolled in the VA and DoD registries suggest the possibility of a neuropsychological component to their health problems. The self-reported exposures of troops to chemicals with potential neurological effects (such as PB, many of the pesticides, the insect repellent DEET, the insecticide permethrin, and potentially organophosphate chemical weapons) also suggest that neurological and neuropsychological outcomes may be important.

The simultaneous or sequential administration of certain compounds (for example, PB and the insect repellent DEET) conceivably could interact to produce an additive or synergistic neurologic effect. However, previous research has indicated that PB does not persist in the body and, therefore, is unlikely to cause any long-term effects (Breyer-Pfaff et al, 1985). Furthermore, it is unlikely that significant simultaneous exposure to PB and insecticides/repellents occurred. PB was most likely used during Operation Desert Storm lasting from late January to late February 1991. Insecticides and repellents, however, were most likely used during the summer months when insects are a particular problem. During the winter insects generally are not a problem that would lead to significant personal application of insecticides and repellents.

With respect to PB alone, the IOM panel concluded that PB is a well-studied medication belonging to a class of drugs about which extensive knowledge exists and that PB could interact with other compounds to cause acute and short-term problems, but was unlikely to cause chronic effects.

The determination that chemical agents (sarin in particular) were present in a munitions depot destroyed by US troops in Khamisiya, Iraq, on March 4 and March 10, 1991 has raised the possibility of exposure to chemical agents of these troops. Allied bombing of chemical weapons storage sites in Muhammadiyat and Al Muthanna has also raised concerns. Thus far, model calculations (CIA, 1996) of plumes from these events predict potential troop exposures at levels that would not likely have caused any acute effects. However, model calculations of the March 10 detonation are not complete. Further assessments of risk at Khamisiyah await these results. Regardless of the outcomes of the exposure models, there is the underlying question of whether exposure to anticholinesterases, such as organophosphate pesticides and chemical agents, at low, sub-clinical levels can produce chronic effects.

The Armed Forces Epidemiology Board (AFEB) has provided a report to DoD (AFEB, 1996) on their assessment of the potential long-term effects resulting from sub-clinical exposures to chemical agents. The report concludes that the scientific literature provides no scientific evidence that acute sub-clinical exposures to either sarin or mustard can result in long-term health consequences. However, the report cites one study (Burchfield et al, 1976) which has shown in primates long-term alterations in electroencephalogram (EEG) following low-level sarin exposure. It was unclear in the paper, however, whether these low-level exposures resulted in any acute effects. Because of this the AFEB report recommends that further research (using primate models) on the long-term EEG effects of sub-clinical and clinical doses of sarin. The AFEB acknowledges in its report that the meaning of these EEG changes is uncertain.

In 1994, about 600 people in Matsumoto, Japan were poisoned with sarin by terrorists. Morita et al (1995) followed 264 people who had sought treatment. Despite frank, acute, and objectively measurable effects consistent with an acute sarin exposure, virtually all of these individuals recovered within three months with no apparent sequelae.

Despite such reassurances, there is still some uncertainty regarding long-term effects from very low, sub-clinical exposures to cholinesterase inhibitors. If there are persistent effects, it is likely they would be manifested in neuropsychological and neurological deficits.

RESEARCH QUESTION 16
Is there a greater prevalence of organic neuropsychological and neurological deficits in Persian Gulf veterans compared to appropriate control populations?

Early studies of neuropsychological and neurological outcome suggest that self-selected Persian Gulf veterans demonstrate subtle differences from controls. Goldstein et al (1996) found that Persian Gulf Registry participants may have small, clinically insignificant neuropsychological deficits which could be related to the presence of psychological comorbidity. A study by Jamal et al (1996) found that Persian Gulf veterans who self-report with symptoms shows evidence of small alterations in peripheral nervous system function. However, these findings are probably confounded by several biases, including that of selection.

A study has been conducted of the acute interactions of PB, DEET, and permethrin when administered orally to rats (US Army, 1995). The endpoint studied was lethality at very high doses. They found potential synergism of effect when PB was combined with DEET and permethrin. More recently, a study by Abou-Dohia et al (1996) indicates that at high, non-lethal doses, there are acute synergistic neurotoxic effects in a chicken model. The relevance of high dose acute toxicity studies to the potential for chronic effects from acute low-level exposures is unknown.

A pilot clinical program at the Birmingham, Alabama, VA Medical Center has conducted neuropsychological tests on veterans from the VA Persian Gulf Registry who self-report exposure to environmental hazards including chemical weapons. Preliminary evidence (Kotler-Cope et al, 1996) does not show any pattern to indicate a common, identifiable neuropathologic process.

Research Underway

PROJECTS VA-2, 4A, 5A, 6-Core; DoD-1A, 1E, 32, 40; HHS-1: Prevalence of symptoms associated with neuropsychological and neurological deficits will be estimated, compared to an appropriate control population, and assessed in relation to significant subgroups of the veteran population, including those self-reporting specific exposures. DoD-40 does not investigate prevalence but is a longitudinal study to examine the time course of neuropsychological function in veterans with PTSD.

PROJECTS VA-4A, 4B, 5, 6A, 9, 10, 11: Components of these projects administer specific neuropsychological and neurological tests to groups of Persian Gulf veterans and Persian Gulf era veterans.

PROJECT VA-4A, 4B: In addition to research focusing on Persian Gulf veterans, investigators at the Boston VAMC Environmental Hazards Research Center are collaborating with scientists at St. Luke’s Hospital in Tokyo, Japan. They are studying the long-term consequences of sarin exposure in individuals hospitalized following the terrorist incident in the Tokyo subway in June 1995. This should provide additional insight into long-term consequences from low-level exposures. The Boston VAMC researchers are also collaborating with scientists in Denmark who are studying Danish Persian Gulf veterans.

PROJECTS DoD-7A: This project will utilize a rat model to investigate the potential effects of depleted uranium on the nervous system.

Additional Research Needed

Epidemiological investigations (if feasible) of the health of Persian Gulf veterans present at the detonation of the weapons depot at Khamasiyah in March 1991;

Epidemiological investigations (if feasible) of the long-term effects of acute exposure to low-levels of chemical warfare agents;

Toxicological investigations of the potential for long-term effects resulting from low-level exposures to chemical agent insufficient to induce acute effects;

Development of a long-term strategic plan for research into the potential long-term health consequences of exposure to low-levels of chemical agents.

RESEARCH QUESTION 17
Can short-term, low-level exposures to pyridostigmine bromide, the insect repellent DEET, and the insecticide permethrin, alone or in combination, cause short-term and/or long-term neurological effects?

Statements that PB alone is safe and well tolerated are supported by a recent DoD-sponsored study (US Army, 1996) that investigated the side-effects of pyridostigmine bromide administered to healthy male and female volunteers in a double-blind protocol. PB (30 mg every 8 hours) or placebo was administered for 21 days (plus one dose). Anticipated side effects in the PB groups were observed although they ocurred in only a few subjects and were generally mild. Four out of 60 subjects receiving PB experienced diarrhea and abdominal pain. The gastrointestinal side effects are consistent with the muscarinic effects of PB. There were no differences in side effects between males and females. Vital signs, laboratory tests, and ECG were not different between PB and placebo groups. A one year follow-up showed no adverse long-term effects. A single subject was diagnosed shortly after the dosing phase with a Fixed Drug Eruption that resolved with topical steroid treatment. The IOM panel recommended that the possibility of chronic neurotoxic effects from short-term low dose administrations needs to be tested in appropriate animal models (IOM, 1995; see Section 4.2, Health Outcomes).

Research Underway

PROJECT DoD-2: In addition to examining physiological and neurobehavioral effects of simulated pollutant exposures, laboratory animals will be tested with pollutants alone and in combination with PB.

PROJECTS DoD-21, 33: These projects investigate blood cholinesterase and the possible role variability in cholinesterase levels might play in predisposing some individuals to adverse reactions to otherwise low doses of anticholinesterases.

PROJECT DoD-37: This project is investigating the possible neurobehavioral and immunological responses of male and female rats to various combinations of PB, DEET, and permethrin.

PROJECT VA-5D: This project is investigating the interactive effects of pyridostigmine bromide and stress in a stress-sensitive animal model.

PROJECT VA-6C: This project is investigating in-vitro the combined neural effects of hydrocarbon solvents and pyridostigmine bromide.

PROJECTS VA-4A, 4B, 5A, 6A: Components of these projects are examining a variety of neurological and neuropsychological endpoints on selected cohorts of Persian Gulf veterans and Persian Gulf era veterans. Endpoints being examined range from nerve conduction velocity studies, to olfactory evoked potentials, to performance on computerized neurobehavioral test batteries. Results will be related to potential self-reported exposures to neurotoxic compounds.

Additional Research Needed

The ongoing clinical and toxicological studies will determine the need for additional studies.

4.2.7 Psychological/Psychiatric Outcomes

A variety of symptoms have been reported by Persian Gulf veterans. Some symptoms may be related to post-traumatic stress disorder (PTSD). Published findings (Sutker et al, 1993; Sutker et al, 1994a,b; and Wolfe et al, 1993) suggest an increased prevalence of PTSD and other psychiatric diagnoses, such as depression, in some Persian Gulf veterans. Ursano and Norwood (1996) provide a comprehensive review of this issue. Although the prevalence of psychiatric disorders has been found to be lower in Persian Gulf veterans than among Vietnam veterans, it is evident that stressors during the Persian Gulf conflict were sufficient to cause significant psychiatric morbidity. Because of the low-level of combat experienced by many troops in the Persian Gulf conflict, the presence of psychiatric problems among some returnees suggests the importance of stress other than actual combat as a precipitating factor. All three review panels (DSB, NIH, and IOM) recognized unusual stressors (e.g., sudden deployment, crowded living conditions, threat of CBW, combat) associated with the deployment and the possibility of their effects on mental health. Additionally, the potential effect of psychological stress on the immune system needs to be considered.

RESEARCH QUESTION 18
Do Persian Gulf veterans have a significantly higher prevalence of psychological symptoms and/or diagnoses than do members of an appropriate control group?

In a study of 1498 Seabees (Kaiser et al, 1995), service members who had been deployed to the Persian Gulf had higher scores on abnormal psychological variables.

Research Underway

PROJECTS VA-2, 4A, 5A, 6-Core, 7, 8, 12; DoD-1A, 1E, 6B, 30, 39, 40; HHS-1, 2: Components of these projects are collecting survey questionnaire data from which extensive questioning will allow development of prevalence estimates of psychological symptoms and diagnoses in comparison to an appropriate control. DoD 30 and DoD-39 will be focusing on women veterans and British veterans respectively. DoD-40 does not determine symptom or illness prevalence but is a longitudinal study of PTSD. Investigators with the Boston VAMC Environmental Hazards Research Center have established collaborations with Japanese scientists to look at psychological/psychiatric outcomes in persons exposed to sarin in the Tokyo subway terrorist incident of June 1995. These investigators are also collaborating with Danish scientists who are studying Danish Persian Gulf veterans.

PROJECTS VA-4A, 5C, 6B: Components of these projects are examining the relationship between symptoms/symptom complexes (such as chronic fatigue syndrome) and the presence of any psychological symptoms and/or diagnoses.

PROJECT VA-4A, 5B, 5C: Components of these projects investigate the immunological status among different symptomatic groups of Persian Gulf veterans. Relationships between psychological stress and altered immune function are being explored.

Additional Research Needed

The ongoing epidemiological and clinical studies will determine what, if any, additional studies are required.

4.2.8 Infection

Leishmaniasis

Unlike veterans with less well-defined illnesses, all but one of 12 veterans diagnosed with viscerotropic leishmaniasis had objective signs of disease, including high fever, lymphadenopathy and hepatosplenomegally. Nevertheless, because of the possibility of subclinical infection and the late presentation of this disease due to the prolonged incubation period, all three review bodies recommended further studies on detection and treatment of leishmaniasis. The IOM Committee recommended that when a serological test or other easy-to-use screening test(s) becomes available, an epidemiological and seroepidemiological study of leishmaniasis in Persian Gulf veterans should be conducted with appropriate controls. Although it appears now that infection with L. tropica is probably not a major risk factor for Persian Gulf veterans’ illnesses, maintaining the current research effort is of value for potential concerns related to future deployments, and for taking advantage of research opportunities that could arise in the future.

Other Infections

Other infectious agents, such as mycoplasmas, bacteria, viruses, and fungi, are unlikely. Nevertheless, in spite of the absence of a strong case from clinical evaluations to support infectious agents as possible etiologic factors, targets of opportunity for collecting serological data should be exploited.

RESEARCH QUESTION 19
What is the prevalence of leishmaniasis and other infectious diseases in the Persian Gulf veteran population?

Research Underway

PROJECT VA-5A: As a component of this project, blood mononuclear cells from Persian Gulf veterans (from existing study populations) will be tested for reactivation for Epstein-Barr Virus, Cytomegalovirus, herpes-6, and herpes-7. Comparisons with appropriate control populations will be made.

PROJECT VA-15,16: These projects are directed at treatment and prevention of leishmaniasis.

PROJECT DoD-8A, 38: In DoD-8A a recombinant antigen has been characterized that detects immune response in patients with viscerotropic leishmaniasis. DoD-38 is also focusing on the development of skin and serologic assays for leishmaniasis.

PROJECT DoD-9: This project is attempting to identify the gene in humans that controls for tropism of L. tropica with the hope of determining which Persian Gulf veterans, with latent L. tropica infection, are at risk for developing disease in the event of future immune suppression.

PROJECT DoD-12: This project involves the development of a forward-deployable infectious disease diagnostic laboratory.

PROJECT DoD-13: This project is examining dogs that were in the Persian Gulf theater to determine if they have any infections of importance to humans.

PROJECTS DoD-42, 47: These projects are investigating whether mycoplasma infection can be detected in individuals from a sample of Persian Gulf War veterans in comparison to a control group.

Additional Research Needed

Because adequate serologic testing is not currently possible, the true prevalence of L. Tropica infection cannot be estimated. If such a test becomes available, seroepidemiologic studies may be undertaken. If feasible and practical, sera should be stored in expectation of such studies.

4.2.9 Cancer/Neoplastic Disease

The occurrence of some cancers among Persian Gulf veterans, although infrequent, has elevated concern over the possibility that these cancers may be linked to service in the Persian Gulf. The DSB, in examining the VA Persian Gulf Registry data, found no discernible demographic, military, or pathological pattern to the distribution of cancer cases (DSB, 1994). However, the DSB pointed out that any conclusions based on the Persian Gulf Registry must be made with caution because it is a self-selected group of veterans. The DSB also pointed out that because of the long latency period associated with cancer originating from environmental causes, it is too early to evaluate cancer risk in Persian Gulf veterans.

RESEARCH QUESTION 20
Do Persian Gulf veterans have a greater risk of developing cancers of any type when compared with an appropriate control population?

The mortality experience of Persian Gulf veterans compared with non-deployed era veterans has been investigated (Kang and Bullman, 1996). No disease-specific increase in mortality was observed in the deployed compared with the non-deployed veterans. Specifically, there was no difference in prevalence of death from neoplastic disease between Persian Gulf veterans and Persian Gulf era veterans. It has also been determined that there is no difference in hospitalization rates for neoplastic disease for Persian Gulf veterans compared with era veterans (Coate et al, 1995).

Research Underway

PROJECT VA-4C: A component of this project involves establishing the basis for a cancer surveillance system among Persian Gulf veterans in the state of Massachusetts.

PROJECT DoD-1F: This project is reviewing hospitalization records for both active duty and non-active duty veterans in California.

PROJECT DoD-7B: This project uses a rat animal model to investigate the carcinogenic potential of embedded depleted uranium fragments.

Additional Research Needed

A system for examining cause-specific, long-term mortality among Persian Gulf veterans (see below) will be useful in providing information on future cancer mortality rates among Persian Gulf veterans.

4.2.10 Mortality Outcomes

RESEARCH QUESTION 21
Are Persian Gulf veterans experiencing a mortality rate that is greater than that of an appropriate control population? Are specific causes of death related to service in the Persian Gulf?

The cause-specific mortality experience of 695,292 service members deployed to the Persian Gulf during Operations Desert Shield/Desert Storm between August 1990 and April 1991 was compared to 746,038 non-deployed US service members (Kang and Bullman, 1996). Follow-up of these veterans covered the period beginning May 1, 1991, or the date they left the Persian Gulf area alive, and September 31, 1993. During the defined period there were a total of 1,765 deaths from all causes among deployed veterans while the number expected in a comparable US civilian population was 4,011. The observed deaths due to all causes among deployed Persian Gulf veterans was, however, greater than that in a comparable non-deployed military population during the same time period. These excess deaths among deployed veterans are primarily attributed to external causes, including all types of accidents and motor vehicle accidents. No excess deaths were observed for suicide and homicide among the Gulf veterans. Postservice increases in mortality due to external causes have been previously documented (Boyle et al, 1987). When deaths due to accidents, suicide, and homicide (external causes) were excluded (leaving only disease-related causes of death), the number of deaths among deployed veterans was 337 while the number expected was 382 based on the mortality rate among the non-deployed veterans. The computed disease-related death rates using these data are not different between deployed and non-deployed veterans. Despite the difference in overall mortality between deployed and non-deployed, DoD completed a study (Writer et al, 1995) comparing the one year, in-service mortality experience of service members who served in Operations Desert Shield/Desert Storm to that of service members who served during the same time period but were not deployed to Southwest Asia. No difference in mortality over that period was found. The latter two investigations have only examined mortality rates over short time frames and, thus, cannot be used to draw any definite conclusions about Persian Gulf veterans’ mortality over longer periods of observation time.

Research Underway

None

Additional Research Needed

Mortality experience follow-up at appropriate future time-points.

Investigation of the specific cause(s) of excess deaths by external causes in veterans deployed to war zones. Such an investigation should not be limited to the Persian Gulf War.


5. SUMMARY AND RECOMMENDATIONS

Since the end of the Persian Gulf conflict and the first reports of health problems in Persian Gulf veterans, the federal government has acted to ensure that veterans have access to medical care, can pursue appropriate avenues for compensation, and are informed of the various programs and activities made available to them by the VA and DoD. Research is now moving forward to address important questions, the answers to which will help guide health care professionals in their treatment of Persian Gulf veterans and will enhance our ability to minimize reoccurrence of such phenomena in future deployments. The Working Plan was developed in 1995 to bring coherence to the research efforts being conducted or sponsored by the federal government, and to assist federal decision makers in the pursuit of various research directions.

In the introduction, three goals were articulated for research on Persian Gulf veterans’ illnesses:

Establish symptom and illness prevalence;

Identify risk factors; and

Identify diagnostic, treatment, and prevention methodologies.

The federal government is currently invested in all three goals and has made progress toward achievement of them. There are early indications that Persian Gulf veterans are reporting an excess of symptomatic complaints, but that these are somewhat diffuse in nature and not accompanied by any definite physical pathology. Results of mortality and hospitalization studies indicate that Persian Gulf veterans are not suffering from an excess of life-threatening diseases. It is evident, though, that the greatest need for research at the present continues to be in the area of epidemiology to ascertain symptom/illness/disease prevalence. Without definitive information in this regard it cannot be quantitatively determined whether Persian Gulf veterans are actually experiencing unusual or unexpected health problems; and if they are, the extent of the problem. The VA Persian Gulf Registry and the DoD Comprehensive Clinical Evaluation Program are valuable for revealing the nature of veterans symptoms and illnesses. However, they cannot, by their self-selected nature, reveal the true population prevalence of the reported symptoms and illnesses. Population-based studies are needed to obtain this information.

VA, DoD, and HHS are actively engaged in several population-based studies to determine symptom and illness prevalence. In addition, there are some small, highly focused, epidemiological efforts that are concentrating on ascertaining the prevalence of discernible symptom complexes such as chronic fatigue syndrome. Clinical investigations, as well as these ongoing epidemiological studies, are clearly important. In addition, concerns that arose more than a year ago about adverse reproductive outcomes and sexual dysfunction among veterans and their spouses added a new dimension to the problem. Although all of the major population-based studies have components associated with reproduction and sexual function, the 1995 Working Plan identified a need for studies focused on these particular problems. New projects (DoD-35 and to a certain extent DoD-30) will be addressing reproductive concerns.

As a vital adjunct to population-based studies, quantitative exposure information is needed. If there are findings of excess symptoms and illnesses in Persian Gulf veterans, geographical and temporal exposure data that can be assigned to veterans during their Persian Gulf deployment would greatly improve the prospects for determining an association between exposure and disease. Accurate exposure data has been difficult to obtain, and this will most likely continue to be a problem.

Research aimed at the second and third goals theoretically should wait until findings from population studies are complete. A few population-based studies have begun to yield results while others are scheduled for completion in the next 12 to 24 months. Although research studies aimed at these goals are not currently as important as the population studies, they have not waited for epidemiology findings. Appropriately targeted, parallel studies investigating specific etiologic factors anticipate epidemiology findings. Furthermore, the research questions that need to be posed addressing etiologic factors should have generalizablility beyond the current concerns of Persian Gulf veterans, and thus, address the needs of the third goal, i.e. the identification of diagnostic, treatment, and disease prevention methodologies. This is particularly important because some risk factors originally thought to be important have declined in likelihood as new information has become available.

The important contribution of non-federally funded research addressing common questions is recognized. Research by independent investigators, published in peer-reviewed scientific journals will continue to be evaluated and used in assessing the health consequences of service in the Persian Gulf, as well as adjusting the course of future research.

At the conclusion of the 1995 Working Plan several important specific areas of inquiry for which significant gaps in knowledge existed were listed. These areas of additional inquiry were cited in a Broad Agency Announcement (BAA) issued by DoD in 1995 in response to a Congressional mandate to conduct additional research by federal and non-federal investigators. The BAA sought proposals that were broadly directed toward epidemiology, clinical research, and research on pyridostigmine bromide. In June 1996 the Persian Gulf Veterans Coordinating Board announced the award of 12 new research grants as an outcome of the original BAA. These 12 were selected on the basis of scientific merit by an independent scientific review panel, and on programmatic relevance derived from the specific areas of inquiry identified in the 1995 Working Plan.

As a result of the evolution of our understanding of Persian Gulf veterans’ illnesses, and of events and concerns not known at the time of the 1995 Working Plan (particularly the events at Khamisiyah and the bombings of Muhammadiyat and Al Muthanna), the Research Working Group has identified the following research issues that need further exploration in the near future:

Follow-up of the mortality experience of Persian Gulf veterans, encompassing cause-specific mortality, at appropriate future time-points;

More longitudinal follow-up studies of the health of Persian Gulf veterans, including those with illnesses that are difficult to diagnose;

Critical peer-review of models used to predict exposure concentrations of environmental pollution (such as the Kuwait oil well fires) and chemical warfare agents (such as the demolition of weapons storage sites at Khamisiyah in March, 1991 and aerial bombing of chemical weapons facilities during the air war);

Assessment of the potential for clinical investigations of the health status of the service members in the vicinity of Khamisiyah when weapons bunker 73 and the storage pit were detonated in March, 1991. If deemed possible, such clinical investigations should be carried out.

Additional research on health-related issues arising from the Persian Gulf experience but with potential for more general applicability to future conflicts is also recommended, including:

Investigation of the risk factors for the development of stress-related disorders, including, but not limited to, post-traumatic stress disorder (PTSD);

Investigation of the risk factors responsible for the observed excess mortality due to external causes (e.g., motor vehicle accidents) in veterans of all wars and conflicts;

Exploration of the development of practical, sensitive, and specific biomarkers of exposure to chemical agents, including organophosphate nerve agents and vesicants such as sulfur mustard.

Toxicological and, where feasible, epidemiological research on the potential for long-term health effects resulting from low-level, sub-clinical exposures to chemical agents, particularly organophosphate agents such as sarin;

Development of a strategic plan for research into the potential long-term health consequences of exposure to low-levels of chemical warfare agents;

If a simple, sensitive and specific, as well as economical, test for L. tropica infection becomes available, seroepidemiologic studies may be undertaken in Persian Gulf veterans. Indeed, when feasible and practical, sera of veterans should be stored in expectation of the possibility for such studies. Despite the declining importance of L. tropica as a risk factor in Persian Gulf veterans, continued research on tests for L. tropica infection are valuable for potential future deployments.

It is anticipated that results from ongoing studies will become increasingly available during the coming year. Because of the limited and focused nature of these studies, it is essential that a contextual framework for evaluating these results be provided in order to maximize the value of results. Therefore, it is further recommended that researchers engaged in research on Persian Gulf veterans’ illnesses be brought together in the coming year for the purpose of comparing results and developing strategies for further meaningful comparisons of results.

Just as this revision of the Working Plan was made necessary by advances in our understanding and new factual information in the past year, it is anticipated that the Working Plan will require periodic revision and updates in the future.


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Sutker PB, Uddo M, Brailey K, Vasterling JJ, Errera P. Psychopathology in war-zone deployed and nondeployed Operation Desert Storm troops assigned graves registration duties. Journal of Abnormal Psychology, 103(2):383-390, 1994b.

Ursano RJ, Norwood AE (Eds). Emotional aftermath of the Persian Gulf War - Veterans, families, communities, and nations. American Psychiatric Press, Inc. (Washington, DC). 1996.

US Army. Acute Oral Toxicity Study of Pyridostigmine Bromide, Permethrin, and DEET in the laboratory rat. US Army Center for Health Promotion and Preventive Medicine Report; Toxicological Study 75-48-2665; May 31, 1995.

US Army. A study to evaluate the safety, Tolerance, pharmacokinetics and pharmacodynamics of pyridostigmine when given in single and multiple doses to males and females in different weight groups. US Army Medical and Materiel Command; Report 94-09; April, 1996.

USAEHA (US Army Environmental Hygiene Agency). Final Report-Kuwait oil fire health risk assessment. No. 39-26-L192-91, 5 May - 3 December 1991. Aberdeen Proving Ground, MD, 1994.

Wolfe J, Brown PJ, Kelley JM. Reassessing war stress: Exposure and the Persian Gulf war. Journal of Social Issues. 49(4):15-31, 1993.

Writer JV, DeFraites RF, Brundage JF. Comparative mortality among US military Personnel in the Persian Gulf region and worldwide during Operations Desert Shield and Desert Storm. JAMA 275:118-121, 1996.


APPENDIX

 

Persian Gulf Veterans’ Illnesses Research Database Index by Agency

DEPARTMENT OF DEFENSE

 
DoD-1AEpidemiologic Studies of Morbidity Among Gulf War Veterans: A Search for Etiologic Agents and Risk Factors;
Study 1: A Study of Symptoms Among 1500 Seabees
A-1
DoD-1B Epidemiologic Studies of Morbidity Among Gulf War Veterans: A Search for Etiologic Agents and Risk Factors;
Study 2: A comparative Study of Hospitalizations Among Active-duty Personnel Who Participated in the Gulf War and Similar
Personnel Who Did Not
A-2
DoD-1C Epidemiologic Studies of Morbidity Among Gulf War Veterans: A Search for Etiologic Agents and Risk Factors;
Study 3: A comparative Study of Pregnancy Outcomes Among Gulf War Veterans and other Active-duty Personnel
A-3
DoD-1D Epidemiologic Studies of Morbidity Among Gulf War Veterans: A Search for Etiologic Agents and Risk Factors;
Study 4: Infertility and Miscarriage in Gulf War Veterans
A-4
DoD-1E Epidemiologic Studies of Morbidity Among Gulf War Veterans: A Search for Etiologic Agents and Risk Factors;
Study 5: Seabee Mail Survey
A-5
DoD-1F Epidemiologic Studies of Morbidity Among Gulf War Veterans: A Search for Etiologic Agents and Risk Factors;
Study 6: A Comparison of Nonfederal Hospitalization Experience Among Veterans in California Who Have Separated From Active Service: PGW vs. EV
A-6
DoD-1G Epidemiologic Studies of Morbidity Among Gulf War Veterans: A Search for Etiologic Agents and Risk Factors;
Study 7: Prevalence of Congenital Anomalies Among Children of Persian Gulf War Veterans
A-7
DoD-2 Physiological and Neurobehavioral Effects in Rodents from Exposure to Pyridostigmine, Fuels, and DEET
(short title: Toxicity of Simulated PGW Exposure)
A-8
DoD-4 The General Well-Being of Gulf War Era Service Personnel from the States of Pennsylvania and Hawaii: A Survey A-10
DoD-6A Combat Stress Pharmacotherapy A-11
DoD-6B Combat Stress Diagnosis, PTSD Prevention A-13
DoD-7A Health Risk Assessment of Embedded Depleted Uranium: Behavior, Physiology, Histology, and Biokinetic Modeling A-14
DoD-7B Carcinogenicity of Depleted Uranium Fragments A-15
DoD-8A Serologic Diagnosis of Viscerotropic Leishmaniasis (VTL) A-17
DoD-8B Development of a Leishmania Skin Test Antigen (LSTA) A-18
DoD-9 Identification of the Genetic Factors Which Control Tropism in Leishmania A-19
DoD-10 Pyridostigmine Synergistic Toxicity Study A-21
DoD-11 Male/Female Differential Tolerances to Pyridostigmine Bromide A-22
DoD-12 Forward Deployable Diagnostics for Infectious Diseases A-23
DoD-13 Effects of Persian Gulf War Service on Military Working Dogs A-24
DoD-14 Risk Factors Among US Army Soldiers for Enrolling on the Department of Veterans Affairs Gulf War Registry A-26
DoD-15 Comparative Mortality Among US Military Personnel Worldwide During Operation Desert Shield and Desert Storm A-27
DoD-16 Kuwait Oil Fire Health Risk Assessment A-28
DoD-17 Retrospective Studies Involving Military Use of Pyridostigmine as a Pretreatment for Nerve Agent Poisoning A-29
DoD-18 Kuwait Oil Fires Troop Exposure Assessment Model (TEAM) A-30
DoD-19 Persian Gulf Veterans Health Tracking System A-31
DoD-20 A Statistical Study Correlating the Reported Cases of Gulf War Syndrome to Battlefield Locations of Afflicted US
Army Personnel During the Iraq-Kuwait War; Part 1: Method to Related Troop Deployment and the
Reported Cases of Gulf War Syndrome and Probable Incidence of Maladies Defined by the ICD-9-CM
A-32
DoD-21 Variability in Pyridostigmine Inhibition of Blood Cholinesterases in Healthy Adults and Individuals with Symptoms
Following Participation in Operation Desert Storm
A-33
DoD-22 Chronic Organophosphorus Exposure and Cognition A-34
DoD-23 Acute and Long-Term Impact of Deployment to Southwest Asia on the Physical and Mental Health of Soldiers and
Their Families
A-36
DoD-30 Epidemiological Studies of Persian Gulf War Illnesses, Persian Gulf Women's Health Linkage Study A-38
DoD-31 Dysregulation of the Stress Response in the Persian Gulf Syndrome A-39
DoD-32 Neuropsychological Functioning in Persian Gulf War Veterans A-40
DoD-33 Effects of Pyridostigmine in Flinders - Line Rats Differing in Cholinergic Sensitivity A-42
DoD-34 Characterization of Emissions from Heaters Burning Leaded Diesel Fuel in Unvented Tents A-43
DoD-35 Feasibility of Investigating whether there is a Relationship Between Birth Defects and Service in the Gulf War A-44
DoD-36 Fatigue in Persian Gulf Syndrome - Physiologic Mechanisms A-45
DoD-37 Neurobehavioral and Immunological Toxicity of Pyridostigmine, Permethrin, and DEET in Male and Female Rats A-46
DoD-38 Diagnostic Antigens of Leishmania tropica A-47
DoD-39 A Controlled Epidemiological and Clinical Study into the Effect of Gulf War Service on Servicemen and Women of the United Kingdom Armed Forces A-48
DoD-40 Psychological and Neurobiological Consequences of the Gulf War Experience A-49
DoD-41 Evaluation of Muscle Function in Persian Gulf Veterans A-50
DoD-42 The Symptomatic Persian Gulf Veterans Protocol: An Analysis of Risk Factors with an Immunologic and .Neurologic Assessment A-51
DoD-44 Investigation of Seminal Plasma Hypersensitivity Reactions A-53
DoD-45 Health and Psychological Readjustment of Gulf War Women A-54
DoD-46 Exploratory Data Analysis with the CCEP Database A-55
DoD-47 Study of Mycoplasmal Infections in Gulf War Veterans A-56
DoD-48 Assessment of Genomic Instability via Chromosome 7 Inversion Frequency in a Gulf-War Syndrome Cohort vs
Selected Control Groups
A-57

 

DEPARTMENT OF HEALTH AND HUMAN SERVICES

 
HHS-1 Health Assessment of Persian Gulf War Veterans from Iowa A-58
HHS-2 Centers for Disease Control and Prevention (CDC) Investigation of Veterans in Pennsylvania A-59
HHS-3 Biomarkers of Susceptibility and Polycyclic Aromatic Hydrocarbon (PAH) Exposure in Urine and Blood Cell DNAfrom
U.S. Army Soldiers Exposed to Kuwaiti Oil Well Fires
A-60
HHS-4 Suspected Increase of Birth Defects and Health Problems Among Children Born to Persian Gulf War Veterans In
Mississippi
A-61

 

DEPARTMENT OF VETERANS AFFAIRS

 
VA-1 Mortality Follow-up Study of Persian Gulf Veterans A-62
VA-2 National Health Survey of Persian Gulf Veterans A-63
VA-3 Use of Roster of Veterans Who Served in Persian Gulf Area A-64
VA-4A Evaluation of Cognitive Functioning of Persian Gulf Veterans A-65
VA-4B Evaluation of Neurological Functioning in Persian Gulf Veterans A-67
VA-4C Gulf War And Vietnam Veterans Cancer Incidence Surveillance A-68
VA-4D Evaluation of Respiratory Dysfunction among Gulf War Veterans A-69
VA-4E The Aromatic Hydrocarbon Receptor (AhR) as a Biomarker of Susceptibility A-70
VA-4F Validity of Computerized Tests A-72
VA-5A Health and Exposure Survey of Persian Gulf Veterans A-74
VA-5B Physiological and Psychological Assessments of Persian Gulf Veterans A-75
VA-5C Effects of Exertion and Chemical Stress on Persian Gulf Veterans A-76
VA-5D Effects of Genetics and Stress on Responses to Environmental Toxins A-77
VA-6 CORE Project Portland Environmental Hazards Research Center: Environment, Veterans Health and the Gulf War
Syndrome. Core: Clinical and Epidemiology Research
A-78
VA-6A Portland Environmental Hazards Research Center: Environment, Veterans Health and the Gulf war Syndrome
Project I. Psychosocial, Neuropsychological and Neurobehavioral Assessment
A-80
VA-6B Portland Environmental Hazards Research Center: Environment, Veterans Health and the Gulf War Syndrome
Project II. Clinical and Neuroendocrine Aspects of Fibromyalgia
A-82
VA-6C Portland Environmental Hazards Research Center: Environment, Veterans Health and the Gulf War Syndrome
Project III. Neurotoxicity of Environmental Pollutants and Warfare Agents
A-84
VA-6D Portland Environmental Hazards Research Center: Environment, Veterans Health and the Gulf War Syndrome
Project IV. DNA Damage from Chemical Agents and Its Repair
A-86
VA-7 Desert Storm Reunion Survey A-88
VA-8 Psychological Test Data of Gulf War Veterans Over Time A-90
VA-9 Evaluation of Cognitive Functioning in Persian Gulf War Veterans Reporting War-Related Health Problems A-91
VA-10 Memory and Attention in PTSD A-92
VA-11 Neuropsychological Functioning in Veterans A-93
VA-12 Psychological Assessment of Operation Desert Storm Returnees A-94
VA-13 Neurobehavioral Aspects of Persian Gulf Experiences: A Pilot Study A-96
VA-15 Vaccine-Mediated Immunity Against Leishmaniasis A-97
VA-16 Protective Immunity in Experimental Visceral Leishmaniasis A-98
VA-17 Immunological Evaluation of Persian Gulf Veterans A-100
VA-18 Chronic Gastrointestinal Illness in Persian Gulf Veterans A-101
VA-20 Psychological Adjustment in Operation Desert Shield/Storm Veterans A-103
VA-21 A Comparison of PTSD Symptomatology among Three Army Medical Units Involved in ODS A-105
VA-30 Female Gender and Other Potential Predictors of Functional Health Status Among Persian Gulf War Veterans A-109
VA-36 Stress Symptoms and Their Causal Attribution in Desert Storm Veterans A-111
VA-40 Musculoskeletal Symptoms in Gulf War Syndrome A-112
VA-46 Diarrhea in Persian Gulf Veterans: An Irritable Bowel-Like Disorder A-113