VA Testimony of John R. Feussner, MD before Congress on February 2, 2000

United States Department of Veterans Affairs

STATEMENT OF
JOHN R. FEUSSNER, M.D.
CHIEF RESEARCH AND DEVELOPMENT OFFICER
VETERANS HEALTH ADMINISTRATION
DEPARTMENT OF VETERANS AFFAIRS
BEFORE THE NATIONAL SECURITY, VETERANS AFFAIRS, AND
INTERNATIONAL RELATIONS SUBCOMMITTEE
HOUSE COMMITTEE ON GOVERNMENT REFORM

RESEARCH ON GULF WAR VETERANS' ILLNESSES

February 2, 2000

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 (PGVCB).

In your invitation to this hearing, you indicated that the purpose of the hearing was to examine the pending report of the General Accounting Office (GAO): Gulf War Illnesses: Management Actions Needed to Answer Basic Questions. Indeed, VA commented on the draft report last summer; until today we have not seen the final report. Nevertheless, as I update your Subcommittee on our research concerning Gulf War veterans’ illnesses, I have attempted to incorporate appropriate references and sensitivity to the GAO’s work. While we did not agree with everything the draft report contained six months ago, we do agree that we should continue reviewing these matters as we develop future plans and studies.

Mr. Chairman, 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.

An important function of the RWG is programmatic review of, and recommendation to, funding agencies on research proposals that have been competitively and scientifically reviewed. The RWG continues to work diligently to foster the highest standards of competition and scientific review for all research on Gulf War veterans’ illnesses.

As an operational policy, the RWG works through the line management authority each department maintains over its intramural scientists, extramural research program managers, and budgets.

By drawing together the three Departments (Defense, Health and Human Services, Veterans Affairs), the RWG has been able to develop an overall research strategy, serve as a common forum for researchers to present ideas and findings, and collectively respond to emerging research issues and problems.

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 (IOM), the National Institutes of Health (NIH); the Senate Veterans’ Affairs Committee Special Investigations Unit; several Congressional committees including this Subcommittee; the Presidential Advisory Committee on Gulf War Veterans’ Illnesses; independent scientists; and Gulf War veterans themselves. The RWG has used advice and information from these sources in developing and implementing a research strategy embodied in A Working Plan for Research on Persian Gulf Veterans Illnesses. This strategy was first released in August 1995 and revised in November 1996. These documents resulted in twenty-one research objectives. The RWG is currently developing summary updates of these research objectives, work, which should be finalized prior to the end of this fiscal year. This plan is responsive to the draft recommendation of GAO that we publish an assessment of progress on the 1995-96 research objectives stated in the working plan.

Mr. Chairman, other notable activities and accomplishments of the RWG include:

Production and dissemination of annual reports to Congress on progress and results of federal research activities;
Secondary programmatic review of research proposals submitted to funding agencies;
Presentations by federal and non-federal researchers before the RWG;
Organization of annual meetings for federally-funded researchers;
Organization of an international symposium in conjunction with the Society of Toxicology on the health effects of low-level exposure to chemical warfare nerve agents;
Development of a strategy for research on the health effects of exposure to low levels of chemical warfare nerve agents;
Follow-up investigation of preliminary reports of positive experimental serological tests for leishmaniasis; and
Development of treatment trials for Gulf War veterans.

To date, the federal government is projecting cumulative expenditures of $159 million for Gulf War research from FY 1994 through FY 2000. There are over 150 projects at various stages of completion in the research portfolio on these veterans’ illnesses. In the past two years alone, 30 projects have been added to this portfolio. Research projects have been funded in the categories of basic research and applied research such as clinical epidemiology and population-based epidemiologic research. Thus far, the overall emphasis of research has been in the areas of the brain and nervous system and in symptoms and general health of Gulf War veterans. After these, the greatest research emphasis is in diagnosis. To date, 47 federally funded projects have been completed resulting in a total of 98 peer-reviewed publications in the scientific literature. Government and non-government researchers conduct research on Gulf War veterans’ illnesses. There are currently a total of 116 principal investigators, including 25 from DoD, 38 from VA, 4 from HHS, 32 who are university-affiliated, 5 non-U. S. counterparts, and 12 from non-government organizations other than universities. All projects and their categories are described in complete detail in the Annual Report to Congress for 1998. The next annual report will include research updates through calendar year 1999. We believe that this kind of collaboration within the federal medical and research communities is consistent with that which was recommended in the GAO’s draft report.

Other highlights of the ongoing research efforts on Gulf War veterans’ illnesses include the following:

In early 1997, VA and DoD tasked the Medical Follow-up Agency (MFUA) of the Institute of Medicine to undertake a feasibility study on the potential to do follow-up of individuals at Aberdeen Proving Ground to examine for potential 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 as a part of their research on the health effects of low-level exposure to nerve agents dating back to the 1950s. The MFUA completed the pilot study in 1998 and determined that the full study could be completed. DoD funded the MFUA (#DoD-93) to proceed with the full-scale study, which is currently underway.

Shortly after the June 1996 announcement of the events at Khamisiyah, Iraq, the RWG recommended that DoD fund three scientifically-meritorious projects in the areas of (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 is described in more detail in the Annual Report to Congress on Federally Sponsored Research on Gulf War Veterans’ Illnesses (Projects DoD-49 through 51). We expect that these studies will be completed this year.

The 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 and heat stress, alone and in various combinations.

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 from the scientific community to this request. The DoD subsequently asked MFUA 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 proposal was deemed meritorious by an independent scientific peer-review panel and the RWG recommended to DoD that this project be funded. This project (#DoD-69) is anticipated to be completed this year.

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, musculoskeletal conditions among Gulf War veterans are clearly evident based on the frequency of these conditions among veterans reporting to the VA and DoD registries, and on results of a number of research studies, including CDC’s study of Iowa Gulf War veterans. The federal government sponsors a significant amount of research to better clarify the pathophysiology and clinical significance of musculoskeletal conditions in Gulf War veterans.

Because of the importance of ensuring appropriate and effective treatment for Gulf War veterans’ illnesses, my office formed a planning group and charged it with developing a Program Announcement (a type of invitation for applications) requesting 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. This Program Announcement was issued in January 1998.

As a result of epidemiological findings to date, subgroups of ill Gulf War veterans have been identified for whom trials of potential treatment are appropriate. In the spring of 1998, the VA Cooperative Studies Program initiated planning for two treatment trials, subsequently known as the "ABT" (antibiotic treatment) and "EBT" (exercise-behavioral therapy) trials. Both trials underwent thorough scientific review and were approved for funding only after rigorous external review provided by the Cooperative Studies Evaluation Committee. Patient characteristics for entry into both trials are similar. All veterans who served in the Gulf between August 1990 and August 1991 are eligible for the studies. Patients are considered to have Gulf War Veterans’ Illnesses (GWVI) if they have at least two of three symptoms (fatigue, musculoskeletal pain, neurocognitive dysfunction) that began after August 1990 and that have lasted for more than six months up to the present.

The ABT trial seeks to study 450 Gulf War veterans at 28 sites throughout the U.S. The study initiated patient accession in May of 1999. The primary hypothesis of the study is that antibiotic treatment directed against mycoplasma species will improve functional status of patients with GWVI who are tested as mycoplasma positive at baseline. The total cost of this treatment trial is approximately $13 million. The trial will be completed about one year from now. Preliminary demographic information indicates that 15% of the study participants are women, nearly 20% represent minority groups, 37% have attained an educational level of college or higher, and about 70% are employed. Nearly 85% of patients currently enrolled in the study exhibit all three symptoms of fatigue, pain, and neurocognitive difficulties. Recruitment of Gulf War veterans into the antibiotic trial is proceeding ahead of schedule.

The EBT trial seeks to study 1,356 Gulf War veterans at 20 sites throughout the U.S. The study initiated patient accessions in April of 1999. The primary hypotheses of the study is that both aerobic exercise and cognitive behavioral therapy (CBT) will significantly improve physical function in veterans with GWVI, and that the combination of CBT and exercise will be more beneficial than either treatment would be alone. The cost of this treatment trial is approximately $9.3 million. The trial will be completed on or about December 2001. Thus far, nearly 500 veterans have joined the study.

Both VA and DoD have undertaken new initiatives that are focused on the neurobiology of stress and stress-related disorders. In addition, other new research efforts include:

A total of 14 new projects were initiated in FY 1998/99 as part of the 1997 DoD BAA request for proposals for studies of post conflict illnesses that extend beyond the Persian Gulf War. These studies will 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.
A total of nine new projects were funded in July 1998 as a result of VA and DoD’s request for intramural proposals valued at $5 million for research on the neurobiology of stress. Expected completion dates for these studies range from the year 2000 through 2002.

Mr. Chairman, I will now provide you with an update of the VA National Survey of Persian Gulf Veterans authorized by Public Law 103-446.

As you may recall, the National Survey is designed to determine the prevalence of symptoms and illnesses among a national random sampling of Gulf War veterans. 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 Gulf War era (15,000 Gulf War veterans and 15,000 non-Gulf War 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. Phase II is complete. In Phase III, 2,000 of the 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 are being conducted at 16 VA medical centers and involve specialized examinations including neurological, rheumatological, psychological, and pulmonological evaluations. When the National Survey is complete we will have a much clearer picture of the prevalence of symptoms and illnesses among Gulf War veterans.

The VA’s Office of Research and Development awarded funds for Phase III of the National Health Survey of Persian Gulf Veterans in November 1998. Currently, 16 sites are participating in these physical examinations. A subcommittee of the Cooperative Studies Evaluation Committee (CSEC, a federally chartered advisory committee) scientifically reviewed the protocol for Phase III and recommended funding. This study is scheduled to examine approximately 2,000 veterans, plus 3,000 of their spouses and children. To date, over 1,000 veterans have joined this observational study, and another 1,230 spouses and children have been examined. The study will cost approximately $12 million and will complete patient recruitment in May of 2001.

The medical evaluations in Phase III are designed to determine:

Whether Gulf War veterans have an increased prevalence of the following conditions frequently reported in the literature, compared to a control group of non-deployed veterans: Chronic Fatigue Syndrome (CFS); Fibromyalgia (FM); neurologic abnormalities, including peripheral neuropathy and cognitive dysfunction; post-traumatic stress disorder (PTSD); and measures of general health status.

Whether the specific medical conditions of arthritis, dermatitis, hypertension, bronchitis, and asthma that have been reported as more frequent among Gulf War veterans compared to non-deployed veterans are of greater prevalence among deployed Gulf War veterans upon objective clinical examination.

Whether the prevalence of any of these conditions is greater among the spouses of Gulf War veterans than among spouses of non-deployed veterans.

Whether the prevalence of medical conditions and major birth defects found on a pediatric physical examination in the children conceived after the war is greater for Gulf War veterans than for non-deployed veterans.

Mr. Chairman, one of the GAO draft report’s recommendations addressed the need to compile data on Gulf War veterans, track their health problems and map the care they receive. We believe that our work in implementing the survey required under Pub. L. 103-446 is responsive to the intent of GAO’s draft recommendation.

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:

Ongoing analysis from the Iowa epidemiologic study of Gulf War veterans using standard measures of health status indicate that nearly 90% of Gulf War veterans reported their health status as "good" to "excellent," while the remainder rate their health status as "poor" to "fair." Interim analysis of this population-based cohort of Gulf veterans also indicates that a minority of them (14%) experienced a significant decline in their health status. Declines were noted in physical functioning and social functioning, while mental health scales showed improvement.

Population-based epidemiological studies are showing that Gulf War veterans self-report more symptoms and exposures than non-deployed veterans of the same era. Ongoing and newly-funded projects are directed toward determining whether a causal connection may exist.

Based on VA and DoD mortality studies there does not appear to be more deaths from disease-related causes among Gulf veterans when compared to non-deployed veterans of the same era. VA plans to continue following the mortality trends of these veterans.

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, who remain on active duty, are not experiencing more illnesses of an acuity or 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 sub-study of the hospitalization study shows that infants of Gulf War veterans have not experienced 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 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.

The Baltimore VAMC Depleted Uranium Program team recently published results showing elevated urine uranium excretion by soldiers who had been wounded by uranium shrapnel. The Baltimore VAMC has an ongoing medical surveillance program that is following a cohort of 33 U.S. soldiers wounded while on or in vehicles struck by depleted uranium penetrators during the Gulf War. The presence of retained shrapnel was identified by x-ray. Urine uranium concentrations were measured. The presence of uranium in the urine can be used to determine the rate at which embedded depleted uranium fragments are releasing biologically active uranium ions. Importantly, there is no evidence of a relationship between urine uranium excretion and kidney function. While we have seen no definitive evidence of adverse clinical outcomes associated with uranium exposure, these veterans will remain under continuing medical surveillance.

Recent research studies have provided important information on the interactions of neurotoxins and other exposures. One study indicates that exercise stress can increase the penetration of pyridostigmine (PB) across the blood-brain barrier in mice suggesting the possibility that PB could cause a central nervous system effect. Another published study, however, suggests that PB does not cross the blood-brain barrier in guinea pigs exposed to extreme heat stress. These inconsistent results with different stressors, in different rodent species, suggest that any extrapolation of such results to humans would be premature. Still another research project has reported on the effects of two weeks’ exposure to low doses of PB on the neuromuscular junction. Although ultra-structural examination of the nerve terminal showed degeneration after two weeks of exposure, the effects were reversed following cessation of exposure. The RWG will continue its research on the toxicology of such interactions.

Neurobehavioral studies of Gulf War veterans and control populations suggest that some Gulf War veterans have brain function abnormalities in such areas as memory, cognition, and motor control. The current RWG research portfolio includes seven studies using methods of sophisticated brain imaging such as conventional and functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy, and "SPECT" imaging. In addition, four studies are currently under contract review.

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 (PAH) (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.

Recently, Gulf War veterans have voiced concerns about a possible association between amyotrophic lateral sclerosis (ALS) and service in the war. Although there is no clear indication of an excess rate of ALS among Gulf veterans, the available data could represent an underestimate of the actual rate. Furthermore, preliminary data suggested that the age distribution of cases of ALS in Gulf veterans appeared to be younger than the age distribution of cases of ALS in the general U.S. population. Accordingly, VA is leading a research effort to identify all cases of ALS, or other motor-neuron diseases, occurring among Gulf War veterans. VA is collaborating with DoD, CDC, and various university disease experts to determine the veterans’ health status and to describe their exposures to potential causal and risk factors for ALS, based on clinical examinations at VA or non-VA centers of excellence in neurologic diseases. This initial case-finding effort will take approximately one year and will provide the most definitive information about the rate of ALS among Gulf veterans, and the age distribution of the diagnosed patients.

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

Mr. Chairman, thank you again for permitting me this opportunity to summarize our work to date so that, using science, we may better understand the health problems of Gulf War veterans. You have my assurance that we will continue this effort to resolve or ameliorate health problems in this population to the greatest extent possible.

Mr. Chairman, I will conclude my testimony here and am happy to answer any questions you or other Committee members may have.