VA Testimony of John R. Feussner, MD before Congress on February 24, 1998

STATEMENT OF
JOHN R. FEUSSNER, M.D.
CHIEF RESEARCH AND DEVELOPMENT OFFICER
VETERANS HEALTH ADMINISTRATION
DEPARTMENT OF VETERANS AFFAIRS
BEFORE THE SUBCOMMITTEE ON HUMAN RESOURCES OF THE
HOUSE COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT
RESEARCH ON GULF WAR VETERANS' ILLNESSES

Mr. Chairman and members of the Subcommittee, thank you for this opportunity to discuss the status of the current and projected federal research program on Gulf War veterans’ illnesses. I serve as the Department of Veterans Affairs’ (VA) Chief Research and Development Officer and the Chairperson of the Research Working Group (RWG) of the Persian Gulf Veterans Coordinating Board. Today I will focus my presentation on the strategy and objectives of the RWG.

First, I would like to provide some history of the RWG. The federal research effort on Gulf War veterans’ illnesses involves scientists in federal, academic, and private institutions, in the United States and abroad, whose research is sponsored by VA, the Department of Defense (DoD), and the Department of Health and Human Services (HHS). Each department has distinct, though complementary, capabilities for conducting and sponsoring research on Gulf War veterans’ health issues. In addition, each department has its own appropriations for extramural and intramural general biomedical research.

The primary charge to the RWG is to assess the state and direction of research; identify gaps in factual knowledge and conceptual understanding; identify testable hypotheses; identify potential new research approaches; review research concepts as they are developed; collect and disseminate scientifically peer-reviewed research information; and ensure that appropriate peer review and oversight are applied to research conducted and sponsored by the federal government.

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 research projects. The coordination and management of this large research effort on Gulf War veterans’ illnesses required the establishment of an overall research policy framework linking each Department’s research management hierarchy. To provide this linkage, in 1993 VA, DoD, and HHS formed the "Persian Gulf Interagency Research Coordinating Council". By January 1994, when the Secretaries of VA, DoD, and HHS formed the Persian Gulf Veterans Coordinating Board (PGVCB), the Research Coordinating Council became the Research Working Group (RWG) operating under the auspices of the Coordinating Board. Because of the potential link between environmental factors and Gulf War veterans’ illnesses, the Environmental Protection Agency was asked to be a member of the Research Working Group.

An important function of the RWG is programmatic review and recommendation to funding agencies of research proposals that have been competitively peer reviewed. The RWG works collectively with VA, DoD, and HHS to elucidate agency-specific funding mechanisms to support research in those identified areas. For a specific research funding activity, the responsible funding agency works with and through the RWG to develop a targeted solicitation for research. Proposals that are submitted to the funding agency in response to a solicitation are scientifically peer-reviewed using agency-specific peer-review programs (e.g., DoD/Department of the Army uses a contract with the American Institute of Biological Sciences). Abstracts of peer-reviewed proposals, written reviews of the peer-reviewers, and the scientific merit scores assigned by the peer-reviewers, are provided to a subcommittee of the RWG charged with providing secondary review of proposals for relevance. The information provided is redacted for personal and institutional identifiers so that programmatic review is anonymous. Relevance determinations are guided by programmatic needs articulated through the RWG process. In its secondary review the RWG may re-rank proposals based on relevance, but it will not recommend non-meritorious proposals for funding to any agency.

The RWG continues to work diligently to foster the highest standards of competition and peer-review for all research on Gulf War veterans’ illnesses.

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 budgets.

By drawing the three departments together, the RWG has been able to jointly develop a research strategy, jointly serve as a forum for researchers to present ideas and findings, and jointly respond to emerging research issues and problems. Through the priority setting processes carried on within the RWG, each department is able to independently develop approaches to addressing those priorities. These approaches are then returned to the RWG for joint discussion, resolution, and recommendations. The RWG has served as an umbrella under which the federal government has been able to respond to many research issues outside the context of the RWG’s regular meetings. When emerging research issues arise within an individual department, the RWG is engaged to ensure that each department participates in discussions on the issues. A specific example of this is when DoD made its determinations about the potential for exposure of troops to nerve agent at Khamisiyah. The determination was made through the work of DoD’s Office of the Special Assistant for Gulf War Illnesses. However, DoD immediately engaged the RWG to develop a coordinated research response to this event. The RWG response was the development of an action plan that led in part to the development of DoD’s 1997 Broad Agency Announcement requesting new research on the health effects of low-level exposure to chemical warfare agents and environmental toxins, alone and in combination with one another.

The RWG has guided the federal research portfolio using a number of different sources of input. These sources include results from ongoing research; various expert panels and oversight committees, such as the Institute of Medicine, the Defense Science Board, the National Institutes of Health; Congressional committees including the Human Resources Subcommittee; the Presidential Advisory Committee on Gulf War veterans’ illnesses; independent scientists; and veterans. The RWG has synthesized the advice and information into a research strategy embodied in A Working Plan for Research on Persian Gulf Veterans Illnesses first released in August 1995 and revised in November 1996. The next revision will be available later in Spring 1998.

I want to highlight some of the ongoing research efforts on Gulf War veterans’ illnesses.

Shortly after the June 1996 announcement of the events at Khamisiyah, the Research Working Group acted to recommend funding by DoD of three proposals that had been previously deemed scientifically meritorious but not funded. The three projects are valued at approximately $2.5 million and involve (1) dosimetry research on exposure to sulfur mustard that will enable quantitative determinations of sulfur mustard exposure at short and long-term intervals; (2) research on the toxicokinetics of the nerve agent VX in three species of animals. The results of this research will facilitate animal to human extrapolation of observed effects in animals resulting from controlled low-level nerve agent exposure; and (3) research on the role of genetic expression of cholinesterases in protecting against anticholinesterase nerve agents. Each of these are described in more detail in the Annual Report to Congress on Federally Sponsored Research on Persian Gulf Veterans’ Illnesses for 1996 released in the Spring of last year.

Subsequently, DoD published a four-part broad agency announcement (BAA) to amplify research on low-level chemical warfare nerve agent effects, as well as research on the health effects of other exposures including insecticides, the nerve agent prophylaxis pyridostigmine bromide (PB), and stress. The BAA resulted in funding recommendations for 12 new projects, valued at approximately $12 million, and covering such exposures as sarin, PB, insecticides, psychological stress, and heat stress, alone and in various combinations. Additional projects have been recommended for funding. DoD will announce these new projects at the time of final award.

As part of the BAA the scientific community was asked for proposals for a feasibility study on the conduct of epidemiological research on the possible health outcomes among troops potentially exposed to sarin at Khamisiyah, Iraq in March 1991. Unfortunately, there was no response to this request. The Department of Defense asked the Medical Follow-Up Agency (MFUA) of the Institute of Medicine (IOM) to develop a protocol for conducting such a study. MFUA designed a protocol that was peer-reviewed by a panel of experts assembled by the American Institute of Biological Sciences. The peer-review panel provided a scientifically meritorious score and the RWG recommended to DoD that this project be funded.

In early 1997 VA and DoD tasked the Medical Follow-up Agency of the Institute of Medicine to undertake feasibility studies on the long-term health effects of exposure to chemical warfare nerve agents. This work is focusing on MFUA’s access to cohorts of veterans exposed at Aberdeen Proving Ground as a part of their research on the health effects of low-level exposure to nerve agents dating back to the 1950s. The MFUA informed us that such a project is indeed feasible and they are currently preparing a full proposal for review.

Also in early 1997, the RWG established a small subgroup of experts on the health effects of nerve agents to develop a broad-based research strategy for investigation of the long-term health effects of low-level exposure to chemical warfare nerve agents. This plan will be published in an upcoming Annual Report to Congress on Gulf War veterans’ illnesses research.

The sarin terrorist attacks in Japan provided an opportunity to study the health consequences of a real-life confirmed sarin exposure. A VA researcher, who is also the Director of the VA Boston Environmental Hazards Research Center, has been collaborating with Japanese investigators who have conducted follow-up studies on 18 exposed individuals. These subjects experienced acute (i.e. sudden onset), but mild, symptoms arising from the Tokyo subway sarin attack of 1995. Investigators have studied psychological, neurobehavioral, and neurophysiological outcomes in these subjects using up-to-date techniques. The outcome measures in each of the exposed subjects have been compared with matched non-exposed control subjects. Three papers resulting from this research have been recently published in the scientific peer-reviewed literature. These papers provide new insight into the effects of clinical exposures to sarin 6-8 months following the attack. In comparison with matched controls, the exposed subjects manifested subtle neurophysiological effects that, although they were not clinically significant, do show that sarin can cause effects on the brain some time following recovery from the acute effects.

Although issues around the potential health impacts on our troops of potential low-level exposures to nerve agents are very important to us, there are other exposures and health outcomes of concern as well. For example, the importance of musculoskeletal conditions among Gulf War veterans is clearly evident based on the prevalence of these conditions among veterans reporting to the VA and DoD registries, and on results emerging from a number of research efforts including the Iowa study of Gulf War veterans. The federal research portfolio contains significant research efforts to better clarify the pathophysiology and clinical significance of musculoskeletal conditions in Gulf War veterans. Of particular note are the efforts at the Portland VA Environmental Hazards Research Center investigating the pathophysiology of Fibromyalgia (FM) and the hypothesis that FM is a disease process that accounts for a significant amount of the musculoskeletal symptoms in ill Gulf War veterans. Also of note, the DoD BAA from 1995 provided funds for three new research programs that employ multi-disciplinary approaches to musculoskeletal function in the context of both pain and fatigue.

Because of the obvious importance of ensuring appropriate and effective treatment of Gulf War veterans’ illnesses, the Department of Veterans Affairs, Office of Research and Development formed a Planning Group charged with developing a Program Announcement (a type of request for applications) inviting proposals within the VA system, or in collaboration with DoD, for multi-center trials for candidate treatments of clearly defined medical syndromes or illnesses among subgroups of Gulf War veterans. The Program Announcement was issued in January 1998. In addition, VA and DoD are proceeding with the planning of a joint VA/DoD multi-center treatment trial for Chronic Fatigue Syndrome and Fibromyalgia in Gulf War veterans.

Both VA and DoD have undertaken new initiatives that are focused on the neurobiology of stress and stress-related disorders. These new efforts include:

Part of the 1997 DoD BAA requested proposals for studies of post conflict illnesses that extend beyond the Gulf War. These studies have been requested to address aspects of the wartime experience that create a confluence of cognitive, emotional, and physical factors to produce chronic, non-specific symptoms and physiological outcomes. Proposals submitted in response to this part of the BAA have been reviewed for scientific merit and program relevance. The RWG made its funding recommendations to DoD and DoD expects to announce awards of selected projects soon. Results of this research are expected to provide new insight into the causes of stress-related disorders.
VA and DoD have issued a request for intramural proposals valued at $5 million for research on the neurobiology of stress. Proposals will undergo scientific review by a joint VA/DoD appointed panel of experts, and programmatic review by the RWG. Awards of projects by VA and DoD are expected by July 1, 1998.
In June 1997 VA funded a multi-center cooperative study examining the effectiveness of a computerized battery of neuropsychological tests that could improve the accuracy of the diagnosis of PTSD by enabling the clinician to rule out organic central nervous system dysfunction.
In July 1996 VA funded a new multi-center treatment trial investigating the efficacy of trauma-based group therapy in the treatment of PTSD.
VA issued a Program Announcement in August 1997 requesting proposals for additional multi-center trials of PTSD treatment. Methodologies sought include novel, non-pharmacologic approaches to treatment, with special emphasis on targeted subpopulations such as women and Gulf War veterans.

I will now provide you with an update of the VA National Survey of Persian Gulf Veterans authorized by Public Law 103-446. The Office of Research and Development has awarded funds for Phase III of the National Health Survey of Persian Gulf Veterans and preliminary site selection has begun. A subcommittee of the Cooperative Studies Evaluation Committee (CSEC, a federally chartered advisory committee), scientifically reviewed the protocol for Phase III.

It is expected that physical examinations will begin in the near future. As you may recall, the National Survey is designed to determine the prevalence of symptoms and illnesses among a random sampling of Persian Gulf veterans across the nation. The Survey is being conducted in three phases. Phase I was a population-based mail survey of the health of 30,000 randomly selected veterans from the Persian Gulf era (15,000 Persian Gulf veterans and 15,000 non-Persian Gulf veterans, males and females). The data collection phase is complete and analysis of the data continues. Phase II consisted of a telephone interview of 2,000 non-respondents from Phase I (1,000 from each group) to determine if there are any response differences between respondents and non-respondents. Additionally, 1,000 veterans from each group will be selected for a telephone interview to validate their responses from the mail survey. Phase II is nearing completion. In Phase III the 2,000 veterans who responded to the postal survey and underwent a telephone interview will be invited, along with their family members, to participate in a comprehensive physical examination protocol. These examinations will be conducted at 18 VA medical centers nationwide and involve specialized examinations including neurological, rheumatological, psychological, and pulmonary evaluations. Completion of data collection is anticipated around mid-1999. When the National Survey is complete we will have a much clearer picture of the prevalence of symptoms and illnesses among Gulf War veterans.

We anticipate that the participating medical centers will enroll patients, spouses, and children by May 1, 1998. We are allowing 18 months for completion of all medical evaluations.

From 1994 to the present the RWG has worked to coordinate and direct a diverse research portfolio consisting of 121 projects and a total investment of approximately $115 million. Of these 121 projects, 39 have been completed, 78 are ongoing, and 4 have been newly awarded and are awaiting startup. Additional research projects are at various stages of planning. There are 14 identified research focus areas ranging from the effects of service in the Gulf War on the brain and nervous system to the potential health consequences of low-level exposure to chemical warfare agents. Approximately one-third of the projects are epidemiological, one-third are clinical, and one-third are basic research.

This research program, as well as research outside of the government, has yielded important new information. Some of the highlights of recent research findings include:

Population-based epidemiological studies are showing that Gulf War veterans self-report more symptoms and exposures than non-deployed veterans of the same era. Currently it is not possible to identify a causal connection between the reported symptoms and exposures. However, ongoing and newly funded projects are directed toward determining whether such a connection may exist.
Based on VA and DoD mortality studies there does not appear to be more deaths from disease-related causes among Gulf War veterans when compared to non-deployed veterans of the same era. VA plans to continue following the mortality experience of Gulf War veterans well into the future.
A study of military hospitalizations has shown that, at least among active duty personnel, the rate of hospitalizations of Gulf War veterans did not exceed that of their non-deployed counterparts. This suggests that Gulf War veterans are not experiencing more illnesses of a severity that would lead to hospitalization. To account for potential bias from restricting this study to military hospitals, the investigators are extending their study to include civilian health care facilities.
A substudy of the hospitalization study shows that infants of Gulf War veterans have not been experiencing a greater prevalence of birth defects compared to the infants of non-deployed era veterans. A more focused examination of the rare birth defect known as Goldenhar Syndrome also failed to find any statistically significant difference in prevalence in infants of Gulf War veterans compared to non-deployed era veterans. Further studies of birth outcomes continue to explore this concern.
Recent research studies have provided important information on the interactions of neurotoxins and other exposures. A recent study indicates that stress can increase the penetration of PB across the blood-brain barrier suggesting the possibility that PB could cause a central nervous system effect. Another recently published study suggests that PB may decrease the levels of permethrin in the central nervous system, thus potentially mitigating against an adverse synergistic interaction between these two compounds. The federal government has increased its research investment in research on the toxicology of interactions.
Neurobehavioral studies of Gulf War veterans and control populations suggest that Gulf War veterans have some brain function abnormalities in such areas as memory, cognition, and motor control in comparison to non-deployed era veterans. Some of these deficits can be accounted for by psychological factors.
Two different research groups have independently found that health symptoms in Gulf War veterans may be associated with PTSD symptoms.
A study conducted at the National Cancer Institute examined blood samples drawn from deployed veterans who went to the Gulf immediately after the end of hostilities. Blood samples were collected in Germany and in the Gulf and tested for a marker of exposure to polycyclic aromatic hydrocarbons (a carcinogenic product of partial combustion of petroleum products). The researchers found more markers for PAH exposure in the samples taken in Germany than in the Gulf.

As the research programs of the federal government continue to provide more results, we will substantially increase our understanding of Gulf War veterans’ illnesses, which will, in turn, enhance our ability to diagnose and treat them. In addition, this newly gained knowledge will enhance prevention and intervention of illnesses in participants of future deployments.