Full Text PA-95-067


NIH GUIDE, Volume 24, Number 20, June 2, 1995

PA NUMBER:  PA-95-067

P.T. 34

  Infectious Diseases/Agents 
  Biology, Cellular 

National Institute on Alcohol Abuse and Alcoholism


The National Institute on Alcohol Abuse and Alcoholism (NIAAA)
invites applications on basic, applied, and preclinical studies to
address the basic biology and immunology of ethanol-induced
impairments to host defense against infectious disease.  The NIAAA
seeks innovative studies that utilize advances in alcohol research
and immunology and host defense mechanisms research.  Understanding
the cellular and molecular processes underlying ethanol-induced
impairments of host innate and immune systems will potentially
broaden the scope of therapeutic interventions that might be used to
enhance or restore host defense mechanisms diminished as a result of
excessive drinking.

This program announcement also seeks applications to improve
compliance with medical therapies through behavioral research.
Research applications are needed to address treatment compliance
issues among alcoholics in vaccine trials and medication protocols
and to assess the impact and effectiveness of interventions aimed at
improving adherence to both alcohol and medical treatment regimens.


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, Alcohol Abuse, HIV, and Infectious Disease, is related
to the priority area of alcohol abuse and alcoholism.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238)


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.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) Awards (R29).


Research support may be obtained through applications for a research
project grant (R01), FIRST (R29) Award, exploratory/developmental
grant (R21), and small grant (R03).  Applicants for R01s may request
support for up to five years.  In FY 1994, the average total cost per
year for a new or competing renewal R01 funded by the Division of
Basic Research was approximately $170,000.  Small grants (R03) and
exploratory/developmental grants (R21) are limited to two years for
up to $50,000 per year and $70,000 per year, respectively, for direct
costs.  FIRST Award applications must be for five years.  Total
direct costs for the five-year period may not exceed $350,000, or
$100,000 in any one budget period.  FIRST awards (R29),
exploratory/developmental grants (R21), and small grants (R03) cannot
be renewed, but grantees may apply for R01 support to continue
research on the same topics.

Potential applicants for FIRST awards, exploratory/developmental
grants, and small grants may obtain copies of the specific
announcements for these programs from the National Clearinghouse for
Alcohol and Drug Information, P.O. Box 2345, Rockville, MD
20847-2345, telephone: 301-468-2600 or 1-800-729-6686.


Although NIAAA desires to stimulate research in this area, the
specific amount of funding available for this research area will
depend on the level of annual appropriated funds, quality of research
applications and program priorities at the time of the award.  It is
estimated that approximately $1 million will be available annually
for new and competing awards.


Alcoholism and Infectious Disease

Per capita consumption of alcoholic beverages in 1992 was 2.31
gallons of alcohol (Williams, et al., 1994).  Although it is not
known to what degree excessive consumption of alcohol contributes to
alcohol-related disorders, in that same year approximately 423,000
hospitalizations in short-stay community hospitals specified alcohol
in the first-listed diagnosis and 1,175,000 cases listed any
alcohol-related morbidity (Caces, et al., 1994).  Furthermore,
beginning in 1984, epidemiological data indicate an increasing trend
in the percentage of patients in the latter category.  This may be
due to alcohol-related diagnoses that were discovered only after
hospitalizations for other reasons.  Although the current per capita
consumption figures do not appear excessive, examination of drinking
patterns of earlier studies show that the heaviest drinking five
percent of the population accounts for about 50 percent of total
alcohol consumption, and the heaviest drinking 33 percent accounts
for 95 percent of total alcohol consumption (DHHS 1988).

Alcoholics, as an immunocompromised population, remain vulnerable to
a wide array of new and resurgent infectious diseases despite modern
treatment.  Hepatitis C virus is now recognized as a leading cause of
chronic liver disease and cirrhosis and may have a role in the
pathogenesis of liver injury in alcoholic patients.  Another source
of microbial pathogens arises from the increase in drug resistance of
both hospital- and community-acquired infections.  Multiple drug
resistant organisms, such as tuberculosis, pose a serious public
health threat to alcoholics in treatment and their care-givers.
Alcohol-induced disorders are wide-ranging, and the importance of
infectious disease is gaining prominence as the spectrum of emerging
diseases changes rapidly in our society and environment.

Alcoholism and HIV Infection

Alcoholic patients often show pronounced frequency and severity of
opportunistic infections (OIs).  These infections, such as
tuberculosis (TB), often arise late in the course of HIV disease
secondary to immunosuppression and are the principal cause of
morbidity and mortality in HIV+ patients.  Although alcohol has been
suggested as a cofactor in HIV disease (Bagasra, et al., 1993; Fong,
et al., 1994), there is no conclusive evidence that acute or chronic
ethanol consumption increases susceptibility to HIV infection or
accelerates HIV disease progression.  Strain variations of HIV,
individual differences in susceptibility, and long incubation time
following seroconversion are some of the difficulties in studying
disease progression.  Whether alcohol consumption increases
susceptibility to OIs in HIV+ patients and whether alcohol-induced
immunosuppression is associated with stimulation, expansion, and
perpetuation of disease are important questions to be clarified.

Alcohol and the Immune System

Alcohol, whether consumed chronically or acutely, alters T lymphocyte
functions, immunoglobulin production by B cells, NK cell function,
and neutrophil and macrophage activities (reviewed in MacGregor,
1986).  Studies in animal models demonstrate that ethanol-fed animals
are unable to suppress dissemination of experimental infections that
can result in progressive organ damage and death (Davis, et al.,
1991; Astry, et al., 1983).  Pulmonary infections, pneumonia, and
tuberculosis have the strongest association with alcoholism.  The
incidence of pulmonary infections is higher in alcoholics than in
abstainers, and prognosis appears to be adversely affected by
prolonged, excessive alcohol consumption.  Using the
well-characterized model of Listeria monocytogenes infection in mice,
Jerrells and his coworkers showed that ethanol-consuming mice were
unable to control the bacterial infection regardless of pre-existing
immunity (Saad, et al., 1993).  Their data indicated that
ethanol-depleted lymphocyte populations resulted in the host's
inability to mount a primary immune response and in loss of memory
cells to recall antigens.  These and other similar studies help
identify mechanisms of immunopathology associated with excessive
alcohol consumption that may contribute to improved quality of life
as well as a better understanding of how to treat and prevent these
diseases in alcohol-consuming individuals.

Alcoholism and Innate Host Defense

It is important to examine the interactions between alcohol and
mediators during the early stages of infection.  The role of alcohol
in perturbing host defense mechanisms during the initial phases of
infection, before immunologic responses are evoked, remains to be
clarified.  Factors that participate in such non-immunologic
responses include free radicals, surfactant and cilia properties of
alveoli, opsonins, and adherence molecules.  Understanding the
impairment of specific cellular and molecular mechanisms associated
with excessive alcohol consumption may improve our understanding of
the infectious disease process in alcoholic individuals and lead to
effective treatment and intervention measures.

Basic science areas needing further research include, but are not
limited to, the following:

o  Studies that define the early in vivo events in the establishment
of infection in alcohol-exposed systems and their relationship to
disease progression;

o  Studies that delineate the alcohol-induced depletion and
dysfunction of target tissues and cells;

o  Studies that seek to understand the possible interactions between
alcohol and therapies for OIs and other diseases; and

o  Studies that identify the roles of cytokines in altering
alcohol-impaired immune processes.

Alcohol and Behavior Compliance

Noncompliance with medication protocols has been shown to be
significantly associated with homelessness and alcoholism.  One of
the most alarming aspects of the recent resurgence of TB is the
development of multidrug resistant (MDR) TB.  The threat of spreading
MDR TB arises from the increasing numbers of people who begin
treatment but lapse before the regimen is completed, thus allowing
the bacterium to develop defensive mutations against antibiotics.
The primary objective of studying behavioral issues in treatment
compliance for TB among alcoholics is to assess the impact and
effectiveness of interventions aimed at improving adherence to both
alcohol and TB treatment regimens.  Clearly, there is a gap in our
knowledge of how interventions designed for all ranges of harmful
alcohol use will interact with the additional requirements of
adherence to infectious disease treatment protocols.

Although behavior compliance issues in alcoholics have mainly
revolved around TB medication protocols, behavior compliance
characteristics of alcohol use in patients involved in vaccine and
other clinical trials have not been studied.  Treatment protocols for
vaccines and therapeutics developed to combat HIV and other
infectious diseases must take into account high levels of alcohol use
among the HIV-infected.  Prevalences of alcohol abuse and dependence
appear to be high in HIV-infected subpopulations.  In HIV-infected
homosexual males, sample estimates of lifetime dependence or abuse is
up to 40 percent. In injecting drug users this prevalences is as high
as 80 percent.  The prevalence of HIV infection in alcohol dependent
risk groups is also high.  For examples, three to five percent HIV
infection rates have been found among alcoholics in residential
alcohol treatment settings (without other risk factors), 10 to 13
percent in hospital-based alcohol programs, and up to 50 percent in
indigent and homeless outpatient populations.  Studies on courses of
medical treatment among alcoholics with co-morbid (or who are at high
risk for) infectious diseases, need to be carried out to identify
effective actions by treatment providers, opportune settings, and
social support characteristics that determine successful or
unsuccessful courses of medical treatment.

This program announcement seeks to identify ways to improve
compliance with therapy through behavioral research.  Behavioral
issues may be framed into descriptive and predictive areas.  Examples
of investigations that may be answered by studies developed through
this solicitation include, but are not limited to, the following:

o  Epidemiologic studies to determine the co-morbidity of drinking
problems and tuberculosis;

o  Studying the impact of alcohol relapse on other treatment
protocols, such as AIDS vaccine and therapeutics clinical trials;

o  Development of optimal monitoring/tracking techniques for
adherence of alcoholic patients to medical regimens;

o  Research and testing of community-based interventions to increase
social support for alcohol abstinence and for adherence to medical
treatment protocols; and

o  Dispositional studies on the individual motivation for seeking
medical treatment for infectious disease and on improving general
health skills.


It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in affect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.


Applications are to be submitted on the grant application form PHS
398 (rev. 9/91) and will be accepted at the standard application
deadlines as indicated in the application kit.  Please note that all
AIDS-related applications have a special receipt date and review and
award schedule.  Applications 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, 6701 Rockledge Drive, Room 1040, MSC
7710, Bethesda, MD 20892-7710, telephone 301-435-0714.  The zip code
for express mail is 20817.  The title and number of the program
announcement must be typed in section 2a on the face page of the

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 number 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:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)


Applications that are complete will be evaluated for scientific and
technical merit by an appropriate peer review group convened in
accordance with the standard NIH peer review procedures.  As part of
the initial merit review, all applications will receive a written
critique and undergo a process in which only those applications
deemed to have the highest scientific merit, generally the top half
of the applications under review, will be discussed, assigned a
priority score, and receive a second level review by the appropriate
national advisory council.

Review Criteria

Criteria for scientific/technical merit review of applications for
regular research grants (R01) are as follows:

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  Adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be

The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.

The review criteria for Small Grants (R03), Exploratory/
Developmental Grants (R21), and FIRST Awards (R29) are contained in
their program announcements.


Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding
decisions:  quality of the proposed project as determined by peer
review, availability of funds, and program priority.


Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.

Direct inquires regarding basic research programmatic issues to:

Leslie Isaki, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 402
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 594-6228
FAX:  (301) 594-0673
Email:  LIsaki@willco.niaaa.nih.gov

Direct inquiries regarding treatment compliance research to:

Kendall Bryant, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 505
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-8820
FAX:  (301) 443-8774
Email:  Kbryant@willco.niaaa.nih.gov

Direct inquiries regarding fiscal matters to:

Linda Hilley
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 504
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-0915
FAX:  (301) 443-3891
Email:  LHilley@willco.niaaa.nih.gov


This program is described in the Catalog of Federal Domestic
Assistance No.  93.273.  Awards are made under authorization of the
Public Health Service Act, Sections 301 and 464H, and administered
under PHS policies and Federal Regulations at Title 42 CFR 52,
"Grants for Research Projects;" Title 45 CFR Parts 74 and 92,
"Administration of Grants;" and 45 CFR Part 48 "Protections of Human
Subjects."  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routing education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the phs
mission to protect and advance the physical and mental health of the
american people.


Astry CL, Warr GA, Jakab GJ:  Impairment of poly-morphonuclear
leukocyte immigration as a mechanism of alcohol-induced suppression
of pulmonary antibacterial defenses.  Am Rev Respir Dis 128:113-117,

Bagasra O, Kajdacsy-Balla A, Lischner HW, Pomerantz RJ: Alcohol
intake increases human immunodeficiency virus type 1 replication in
human peripheral blood mononuclear cells.  J Infect Dis 167:78-797,

Davis CC, Mellencamp MA, Preheim LC:  A model of pneumococcal
pneumonia in chronically intoxicated rats. J Infect Dis 163:799-805,

Caces MF, Stinson FS, Dufour MC:  Trends in alcohol-related morbidity
among short-stay community hospital discharges, United States:
1979-92.  Surveillance Report #32.  National Institute on Alcohol
Abuse and Alcoholism, 1994.

Fong IW, Read S, Wainberg MA, Chia WK, Major C:  Alcoholism and rapid
progression to AIDS after seroconversion.  Clin Infect Dis
19:337-338, 1994.

MacGregor RR:  Alcohol and immune defense.  JAMA 256:1474-1479, 1986.

Saad AJ, Domiati-Saad R, Jerrells TR:  Ethanol ingestion increases
susceptibility of mice to Listeria monocytogenes. Alcoholism
17:75-85, 1993.

U.S. Department of Health and Human Services:  The Surgeon General's
Report on Nutrition and Health.  DHHS Publication No. 88-50210.
Washington, DC:  US Government Printing Office.

Williams, GD, Clem, DA, and Dufour, MC:  Apparent Per Capita Alcohol
Consumption:  National, State, and Regional Trends, 1977-1992.
Surveillance Report #31.  National Institute on Alcohol Abuse and
Alcoholism, 1994.


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