Genetic Influences of Albuterol Response In Children With Bronchiolitis
Bronchiolitis is a significant cause of morbidity and hospitalization in children, accounting for approximately 125,000 hospitalizations per year in the U.S. Recently, genetic variations of the β2-adrenergic receptor (β2-AR) have been shown to influence response to β2-AR agonist therapy in children with asthma. We suspect that genetic variations of the β2-AR also affect response to β2-AR agonist therapy in children with bronchiolitis.
|Study Design:||Observational Model: Case-Only
Time Perspective: Prospective
|Official Title:||Genetic Influences of Albuterol Response In Children With Bronchiolitis|
- The primary end point is change in lung resistance following a single dose of inhaled b2-AR agonist therapy (albuterol). [ Time Frame: Immediate ] [ Designated as safety issue: No ]
- To assess the change in lung compliance following a single dose of inhaled b2-AR agonist therapy (albuterol) [ Time Frame: Duration of hospitalization ] [ Designated as safety issue: No ]
- To compare duration of mechanical ventilation and ICU hospital length of stay by genotype [ Time Frame: Duration of Hospitalization ] [ Designated as safety issue: No ]
|Study Start Date:||December 2007|
|Estimated Study Completion Date:||April 2014|
|Estimated Primary Completion Date:||April 2014 (Final data collection date for primary outcome measure)|
Bronchiolitis is a significant cause of morbidity and hospitalization in children, accounting for approximately 125,000 hospitalizations per year in the U.S. Of these hospitalized children, 8% will require intensive care unit (ICU) admission and 67% of these children will require mechanical ventilation. Mortality in previously healthy children is generally low, however, in children with high-risk medical conditions such as prematurity or congenital heart disease, mortality can be as high as 3%. In addition, bronchiolitis infections are associated with long term respiratory problems including development of recurrent wheezing, airway hyperreactivity, and asthma.
Treatment for bronchiolitis is largely supportive. Despite four decades of clinical trials, there are no therapies demonstrated to be effective in shortening either hospitalization or ICU length of stay in children with bronchiolitis. The use of β2-adrenergic receptor (β2-AR) agonists has received the most attention from investigators, however the results of clinical trials have been contradictory and inconclusive.
Recently, investigators have shown that genetic factors have important influences on a patient's response to β2-AR agonists. Single nucleotide polymorphisms (SNP) at amino acid position 16 of the β2-AR gene are thought to be the most functionally relevant. A change at base 46 from adenine to guanine results in the amino acid sequence of the β2-AR containing a glycine (Gly), rather than an arginine (Arg), at amino acid position 16. Patients homozygous for Gly at this position (Gly/Gly) have been shown to have improved response to β2-AR agonist therapy when compared to children homozygous for Arginine (Arg/Arg) or heterozygous (Arg/Gly). The next most common polymorphism of the β2-AR gene, glutamine to glutamic acid at position 27 (Glu27Gln), may be associated with the development of asthma and airway hyperresponsiveness, but these relationships are less clear.
We believe that genetic factors also influence response to β2-AR agonist therapy in children with bronchiolitis. Specifically, we believe that β2-AR polymorphisms at amino acid position 16 affect response to acute β2-AR agonist therapy in children with bronchiolitis. Our hypothesis is that children with bronchiolitis who are homozygous for glycine at amino acid position 16 (Gly/Gly) will have improved response to inhaled β2-AR agonist therapy.
|United States, Connecticut|
|Connecticut Children's Medical Center|
|Hartford, Connecticut, United States, 06106|
|Principal Investigator:||Christopher L Carroll, MD||Connecticut Children's Medical Center|