EXERCISE-INDUCED FATIGUE IN CHRONIC FATIGUE SYNDROME NIH GUIDE, Volume 21, Number 11, March 20, 1992 PA NUMBER: PA-92-55 P.T. 34; K.W. 0715043, 0745030, 0765033, 0745020 National Institute of Allergy and Infectious Diseases PURPOSE The National Institute of Allergy and Infectious Diseases invites investigator-initiated research grant applications to explore biologically rational hypotheses concerning exercise-induced fatigue and/or pathogenesis in chronic fatigue syndrome (CFS) patients. The purpose is to gain an understanding of the biologic basis of CFS in humans. Such an understanding could lead to the development of diagnostic markers and therapeutic interventions. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This program announcement, Exercise-Induced Fatigue in Chronic Fatigue Syndrome, is related to the priority area of immunization and infectious diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-0325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Research grant applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Applications from minority individuals and women are encouraged. Foreign institutions are not eligible for the First Independent Research Support and Transition (FIRST) award (R29). MECHANISMS OF SUPPORT Applications considered appropriate responses to this announcement are the traditional research project grant (R01) and the FIRST Award (R29). RESEARCH OBJECTIVES o Background CFS is a multisystem syndrome suspected to be triggered by viral infection and characterized by months of debilitating fatigue frequently associated with sore throat, low grade fever, myalgia, headache, gastrointestinal symptoms, and tender lymph nodes. Cognitive deficits, symptoms of depression, and sleep disorder have been reported, and abnormal brain images derived by different techniques have been described. CFS patients are reported to have neuroendocrine response patterns that differ from those of controls. CFS is diagnosed more frequently in women than in men. Patients have a high prevalence of allergies and profiles of T-cell subsets indicate a state of immune activation in severely ill patients. There have been numerous reports of specific immune dysfunctions, but no single impairment has been regularly associated with the syndrome. Similarly, viruses from several taxonomic groups have been reported to be involved, but none as yet has been confirmed to be consistently associated with disease onset or progression. Many clinical investigators consider the profound fatigue induced by exercise to be an essential feature of the illness. Studies that follow-up on this clinical observation have the potential to provide important insights into the underlying pathogenic mechanisms of CFS. o Research Objectives and Experimental Approaches Well-controlled studies with adequate sample sizes are sought to uncover the basis for the debilitating fatigue that follows moderate exercise in CFS patients. For example, it has been postulated that exercise triggers an acquired or inherent exaggerated cytokine responsiveness. This hypothesis is amenable to testing in exercise-challenge studies of CFS patients. Studies to develop algorithms for standardized characterization and comparison of cytokine responsiveness are within the scope of this announcement. Animal studies also are sought that attempt to identify factors associated with viral or other infectious diseases, which predispose to the development of exercise intolerance. Development of animal models would provide the opportunity to critically evaluate other hypotheses related to the pathological consequences of an over-reactive cytokine response. In clinical studies, clearly specified inclusion and exclusion criteria for case definition are essential [Holmes, et. al., Annals of Internal Medicine: 108, 387-389, 1988]. The proportion of women in patient study groups should be at least 50 percent. Attention must be given to control for the variables, including disease activity, that impact on the parameters under study. Investigators are referred to a supplement to Reviews of Infectious Diseases that is devoted to considerations in the design of studies of CFS and the choice of methodologies [Reviews of Infectious Diseases, Vol. 13, Supplement 1, January 1991]. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or Principal Investigator must be included with the application. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions that disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 in Section 2, 1-4 of the Research Plan AND summarized in Section 2, E. Human Subjects. Applicants/offerors are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups must be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the review will be deferred until the information is provided. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES Applications are to be submitted on the research grant application form PHS 398 (rev. 9/91) and will be accepted at the standard application deadlines indicated in the application kit. Application kits are available at most institutional business offices and may be obtained from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 496-7441. On the first (face) page, item 2a, of the application, the word "Yes" must be checked and the title and number of the announcement typed in the space provided: PA-92-55: EXERCISE-INDUCED FATIGUE IN CHRONIC FATIGUE SYNDROME. The original and five legible copies of the application should be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW PROCEDURES Applications submitted in response to this announcement will be assigned on the basis of established Public Health Service Referral Guidelines. Applications will be reviewed for scientific and technical merit by study sections of the Division of Research Grants, NIH, and in accordance with the standard NIH peer review procedures. Following scientific-technical review of the applications a secondary review will be by the appropriate national advisory council or board. AWARD CRITERIA Applications will compete for available funds with all other R01 and R29 applications considered to have significant and substantial merit. The following will be considered when making funding decisions: relative scientific merit, program relevance, availability of funds. INQUIRIES Direct inquiries regarding programmatic issues to: Ann Schluederberg, Sc.D. Chief, Virology Branch Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Solar Building, Room 3A16 Bethesda, MD 20892 Telephone: (301) 496-7453 Fax: (301) 402-0804 Direct inquiries regarding fiscal matters to: Mr. Todd Ball Chief, Microbiology and Infectious Diseases GM Section National Institute of Allergy and Infectious Diseases Solar Building, Room 4B35 Bethesda, MD 20892 Telephone: (301) 496-7075 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.856, Microbiology and Infectious Disease Research. Grants will be awarded under the authority of the Public Health Service Act, Title III, Section 301 (Public Law 78-410, as amended; 42 USC 241) and administered under PHS grants policies and Federal Regulations at 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review.