NUTRITION IN CYSTIC FIBROSIS

NIH GUIDE, Volume 22, Number 30, August 20, 1993



PA NUMBER:  PA-93-103



P.T. 34



Keywords:

  Pulmonary Diseases 

  Nutrition/Dietetics 

  Pathophysiology 



National Institute of Diabetes and Digestive and Kidney Diseases



PURPOSE



The National Institute of Diabetes and Digestive and Kidney Diseases

(NIDDK) invites applications for research to assess nutritional

status in cystic fibrosis (CF), the pathophysiology underlying the

nutritional problems associated with cystic fibrosis, and the

contribution of nutritional disorders to morbidity and mortality of

cystic fibrosis, and to develop and/or test interventions to improve

nutritional status, growth and development in cystic fibrosis.



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, Nutrition in Cystic Fibrosis, is related to the

priority area of chronic 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 20402-9325 (telephone 202-783-3238).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic, 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) (R29) award.



MECHANISM OF SUPPORT



The mechanisms of support for this program will be the research

project grant (R01), and FIRST awards (R29).  Although the sizes of

awards may vary considerably from one project to another, it is

anticipated that the average size of an award will be approximately

$220,000 in total costs for the first budget period.



RESEARCH OBJECTIVES



The purpose of this initiative is to stimulate research in

characterizing the nutritional status of children and adults with CF,

improve methods for evaluating nutritional status in CF, understand

the causes of malnutrition in CF, examine the molecular and cellular

consequences of nutritional alterations in CF, define the

relationship of nutritional status to mortality and morbidity in CF,

examine whether or not improved nutritional status will influence

progression of pulmonary disease, and develop strategies to improve

nutritional status, growth and development in CF.



Background



Despite dramatic improvements in lifespan of patients with CF, the

median survival in 1992 was 29 years.  Malnutrition contributes

significantly toward morbidity in CF.  Although malnutrition due to

pancreatic enzyme insufficiency is correctable and 92 percent of U.S.

CF patients take pancreatic enzyme supplements, the majority of CF

patients are underweight and have short stature with half below the

tenth percentiles for height and weight, based on data from nearly

19,000 patients in the Cystic Fibrosis Foundation (CFF) National

Patient Registry, 1991.  Mortality rate and decline in pulmonary

function correlate with poorer weight status after adjusting for age,

sex, and pulmonary function in longitudinal analyses from this

database.  The relationship between pulmonary function and

nutritional status is complex and the extent to which achievement of

normal nutrition and growth might ameliorate the rate of progression

of lung disease and improve survival remains to be determined.

Longitudinal analysis of CF patients is warranted to answer causal

questions.  Improved nutritional status may improve exercise

tolerance and muscle function, possibly improving respiratory muscle

strength, and may have important implications for resistance to

infection.



A variety of methods are now available for assessing body composition

in CF, including bioelectric impedance analysis, dual photon and dual

x-ray absorptiometry, and total body electrical conductivity.

Assessment of energy expenditure and substrate utilization will

permit exploration of questions about the relative contributions of

altered energy needs and intake to malnutrition and growth failure in

CF.  There is evidence that resting energy expenditure is increased

in CF, but the mechanism by which this occurs and the contributions

of lung disease, the genetic defect itself, medications and

inflammation, infection, and other potential factors influencing

metabolism must be elucidated.  In addition to identifying the

mechanisms of altered energy balance, improved methods are needed to

detect patients requiring improved nutritional support, monitor

prospectively the response to nutritional intervention, and assess

the impact of nutritional status on anticipated new therapeutic

strategies.  Moreover, assessment of the impact on nutritional status

of anticipated new therapeutic strategies for CF, including

pharmacologic therapy targeted to the molecular basis of the disease

and gene therapy, will require simple, validated and cost effective

techniques for evaluation of nutritional status.  Areas of

opportunity and new directions for research were identified at a

recent NIDDK/CFF conference on Nutrition in CF and are summarized in

this Program Announcement.



Scope



Some examples of research topics that would be considered responsive

to this solicitation include the following:



1.  The relationship of nutritional status to mortality and morbidity

in CF:



o  how to use anthropometric indices, including height, weight and

skinfold data, parental height, and pubertal stage, most effectively

in longitudinal investigation of CF mortality and morbidity;



o  the nature and basis of male/female discrepancies in CF morbidity

and mortality and of clinical worsening    at adolescence in CF;



o  the impact of critical periods of growth, e.g., infancy and

adolescence, on nutritional status and response to nutritional

intervention in CF;



o  how fitness and nutritional status are related to mortality and

morbidity in CF;



2.  Methods to evaluate nutritional status and identify functional

correlates in CF:



o  validation over the age and disease spectrum of nutritional

assessment tools ultimately of use in the clinical setting in CF,

including both sophisticated methodology and simpler measures;



o  development and analysis of functional correlates of nutritional

status in CF, including exercise tolerance and static and dynamic

muscle function;



o  establish which body composition methods are most useful for

assessment of CF and development of dynamic measures of body

composition change;



o  definition of body compartments of nutritional significance and

correlation with function in CF;



3.  Nutrient absorption and utilization and energy expenditure in CF:



o  evaluation of energy expenditure methods in CF, i.e., for energy

costs of specific activities;



o  evaluation of substrate utilization methods in CF, e.g., protein

and lipid turnover;



o  novel methods to evaluate nutrient absorption and losses in CF;



o  evaluation of methods to assess micronutrient homeostasis in CF;



o  the relative contributions of altered energy loss, energy

expenditure, and energy intake to energy imbalance in CF;



4.  Combined effects of CF and other conditions:



o  the impact of other factors including early screening,

socio-economic status, liver disease, transplantation and pregnancy

on nutritional status in CF;



o  the etiology of insulin deficiency in CF, its effects on protein

metabolism and growth, and optimal methods to assess and manage

diabetes mellitus in CF;



5.  Relationship of respiratory disease to malnutrition:



o  relationship of respiratory muscle strength to malnutrition and to

specific nutrient deficiencies;



o  longitudinal data on respiratory muscle strength in CF with and

without intervention;



o  methods to assess muscle function versus mass in malnutrition;



o  effects of malnutrition on anatomic and functional lung growth;



o  longitudinal analysis of whether prevention of malnutrition and

growth failure ameliorates the rate of progression of lung disease;



6.  Longitudinal analysis of the relationship between malnutrition

and chronic infection in CF:



o  does repeated or chronic infection accelerate malnutrition?



o  are metabolic changes or failure to replete markers for inadequate

treatment of infection?



o  are micronutrient changes a cause or a consequence of

susceptibility to infection?



o  at what level of malnutrition does immunological function

deteriorate?



o  what is the relationship of nutritional status and inflammatory

response, acute phase response, and prostaglandin release causing

vasoconstriction?



o  how does infection influence energy expended?



7.  Strategies to improve nutritional status in CF:



o  prospective evaluation of the effectiveness of interventions

ranging from education to total parenteral nutrition;



o  the risks, benefits and role of growth factors and anabolic

agents;



o  improved enzyme formulations that are acid resistant or without pH

inhibition;



o  the role of micronutrients as pharmacologic agents;



o  specific nutritional supplements such as omega 3 fatty acids or

structured lipids;



o  use of transgenic CF animal models and CF cell lines to explore

the impact of nutritional factors and interventions.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH policy is that applicants for NIH 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

which 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

(rev. 9/91) in Item 4 (Research Design and Methods) of the Research

Plan AND summarized in Item 5, Human Subjects.  Applicants 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 grant application form PHS

398 (rev. 9/91) and will be accepted at the regular application

deadlines as indicated in the application kit.  Application kits are

available at most institutional offices of sponsored research and may

be obtained from the Office of Grants Information, Division of

Research Grants, National Institutes of Health, Westwood Building

Room 449, Bethesda, MD 20892, telephone 301/710-0267.  The title and

number of this announcement must be typed in Section 2a on the face

page of the application.



Applications for the FIRST Award (R29) must include at least three

sealed letters of reference attached to the face page of the original

application.  FIRST Award (R29) applications submitted without the

required numbered of reference letters will be considered incomplete

and will be returned without review.



The completed original application and five legible copies must be

sent or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building Room 240

Bethesda, MD  20892**



REVIEW PROCEDURES



Applications will be assigned on the basis of established PHS

referral guidelines.  Applications will be reviewed for scientific

and technical merit by study sections of the Division of Research

Grants, NIH, in accordance with the standard NIH peer review

procedures.  Following scientific-technical review, the applications

will receive a second-level review by the appropriate Institute's

national advisory council.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications.  The following will be considered in making funding

decisions:



o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  Program balance among research areas of the announcement



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.



Direct inquiries regarding programmatic issues to:



Judith E. Fradkin, M.D.

Division of Diabetes, Endocrinology and Metabolic Diseases

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 621

Bethesda, MD  20892

Telephone:  (301) 594-7567



Direct inquiries regarding fiscal matters to:



Linda M. Stecklein

Division of Extramural Activities

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 653

Bethesda, MD  20892

Telephone:  (301) 594-7543



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance No. 93.847.  Awards are made under authorization of the

Public Health Service Act, Title IV, Part A (Public Law 78-410, as

amended by Public Law 99-158, 42 USC 241 and 285) and administered

under PHS grants policies and Federal Regulations 42 CFR 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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