NIH GUIDE, Volume 21, Number 11, March 20, 1992

PA NUMBER:  PA-92-55

P.T. 34


  Chronic Fatigue 



  Diagnosis, Medical 

National Institute of Allergy and Infectious Diseases


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.


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).


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).


Applications considered appropriate responses to this announcement are

the traditional research project grant (R01) and the FIRST Award (R29).


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


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






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


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.


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:


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**


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.


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.


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


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.


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