We aim to prospectively define how specific genetic, biologic, and immunologic characteristics, along with environmental exposures, interact in children who experience severe RSV bronchiolitis early in life impact the subsequent development of asthma, airway hyperreactivity and allergy. Specifically, we will utilize a well- established cohort of children with severe RSV bronchiolitis that has been prospectively followed since 1998 (RSV Bronchiolitis in Early Life, RBEL-I, n=206), a retrospectively identified cohort of children with severe RSV bronchiolitis (Boston RSV Bronchiolitis cohort, n=200), and test our key findings from RBEL-I in a newly enrolled prospective cohort of infants with severe RSV bronchiolitis (RBEL-II, n=200). These cohorts will be the largest to date, with over 600 children with severe RSV bronchiolitis, and will enable us to test new hypotheses on the causation of asthma and allergic disorders early in life. We will be able to evaluate and confirm over 1500 polymorphisms in candidate genes associated with asthma, airway hyperreactivity, allergic sensitization and RSV susceptibility in three separate populations. We now propose to prospectively test the validity of the newly developed RSV-Asthma Predictive Index (RAPI) in this cohort as well as potentially modify this index to improve its predictive value. We will prospectively evaluate our findings of a dysregulated immune system associated with the development of asthma post-RSV bronchiolitis in RBEL-II. In concert with understanding the biologic and immunologic response of the host during and after severe RSV bronchiolitis, we are now proposing a powerful study of candidate genes associated with susceptibility to RSV and the development of asthma, airway hyperreactivity and allergic sensitization in the combined RBEL and Boston cohorts with over 600 children as well as their parent(s). Given the careful characterization of these children early in life, we will now be able to study potential gene-gene and gene-environment interactions leading to the development of different wheezing phenotypes in childhood. Our overall hypothesis is that children who experience severe RSV bronchiolitis in the context of the appropriate genetic predisposition, have a dysfunctional immune response that predisposes them to develop airway hyperreactivity and asthma. Accordingly, we propose to:
Aim I : Evaluate prospectively the validity of a RSV-Asthma Predictive Index (RAPI) on the development of asthma and persistent wheezing following severe RSV bronchiolitis.
Aim II : Evaluate prospectively the impact of a dysregulated immune system, specifically dendritic and regulatory T cells, on the development of asthma, persistent wheezing and allergic sensitization following severe RSV bronchiolitis.
Aim III : Examine the relationships of ~1500 polymorphisms in genes associated with asthma, atopy, inflammation with the development of asthma, airway hyperreactivity, and allergic sensitization following severe RSV bronchiolitis.

Public Health Relevance

We aim to prospectively define how specific genetic, biologic, and immunologic characteristics, along with environmental exposures, interact in children who experience severe RSV bronchiolitis early in life on the subsequent development of asthma, airway hyperreactivity and allergy. This study will be the largest to date, consisting of over 600 children with severe RSV bronchiolitis, and will enable us to test new hypotheses on the causation of asthma and allergic disorders early in life.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092486-04
Application #
8305036
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Noel, Patricia
Project Start
2009-08-13
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$722,078
Indirect Cost
$190,601
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Beigelman, Avraham; Bacharier, Leonard B (2013) The role of early life viral bronchiolitis in the inception of asthma. Curr Opin Allergy Clin Immunol 13:211-6
Guilbert, Theresa W; Bacharier, Leonard B (2011) Controversies in the treatment of the acutely wheezing infant. Am J Respir Crit Care Med 183:1284-5