Chest

Chest

Volume 135, Issue 5, May 2009, Pages 1186-1192
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Original Research
Asthma
β2-Adrenergic Receptor Polymorphisms Affect Response to Treatment in Children With Severe Asthma Exacerbations

https://doi.org/10.1378/chest.08-2041Get rights and content

Background

β2-adrenergic receptor agonists are the mainstay of treatment for severe asthma exacerbations, one of the most common causes of critical illness in children. Genotypic differences in the β2-AR gene, particularly at amino acid positions 16 and 27, have been shown to affect the response to β2-AR agonist therapy. Our hypothesis is that genotypic differences contribute to patient response to β2-AR agonist treatment during severe asthma exacerbations in children.

Methods

Children admitted to the hospital ICU for a severe asthma exacerbation between 2002 and 2005 were located, and genetic samples were obtained from saliva. Children hospitalized during this period were treated with a protocol that titrated β2-AR therapy (first nebulized, then IV) according to a validated clinical asthma score.

Results

Thirty-seven children hospitalized during the study period were enrolled into the study. At amino acid position 16 in the β2-AR gene, 13 children were homozygous for the glycine (Gly) allele (Gly/Gly), 8 were homozygous for the arginine (Arg) allele (Arg/Arg), and 16 were heterozygous (Arg/Gly). Despite similar clinical asthma scores on hospital admission, the children with the Gly/Gly genotype had significantly shorter hospital ICU length of stay and duration of continuously nebulized albuterol therapy and were significantly less likely to require IV β2-AR therapy than those with Arg/Arg or Arg/Gly genotypes. No association existed among polymorphisms at amino acid position 27 and response to β2-AR therapy.

Conclusions

In this cohort of children with severe asthma exacerbations, children whose genotypes were homozygous for Gly at amino acid position 16 of the β2-AR gene had a more rapid response to β2-AR agonist treatment. The β2-AR genotype appears to influence the response to therapy in this population.

Section snippets

Materials and Methods

This study was approved by the Institutional Review Board at Connecticut Children's Medical Center. Written informed consent was obtained before patient enrollment.

All children between 2 and 18 years of age with physician-diagnosed asthma and who were admitted with a severe asthma exacerbation between January 1, 2002, and December 31, 2005, were included in the study. Severe asthma exacerbations were defined as those requiring hospital ICU admission. Children with chronic medical conditions

Patient Characteristics

During the study period, 149 children were admitted to the hospital ICU for a severe asthma exacerbation. The parents of 90 of these children could be contacted by mail and telephone, and 37 of them consented to enroll their child in this study. At amino acid position 16 of the β2-AR gene, 13 (35%) children were homozygous for Gly (Gly/Gly), 8 (22%) were homozygous for arginine (Arg/Arg), and 16 (43%) were heterozygous (Arg/Gly). At amino acid position 27 of the β2-AR gene, 16 children (43%)

Discussion

In this cohort of children with severe asthma exacerbations, the children whose genotypes were homozygous for the β2-AR genotype were associated with a response to short-term high-dose β2-AR agonist therapy. Specifically, children homozygous for the Gly allele at amino acid position 16 had significantly shorter durations of continuously nebulized β2-AR agonist therapy and shorter hospital ICU length of stays when compared to the rest of the cohort and treated according to a goal-directed

Conclusions

We found that the Gly/Gly genotype of β2-AR was associated with improved response to high-dose β2-AR agonist therapy in children with severe asthma exacerbations. This finding suggests that pharmacogenetics may allow for evidence-based therapy in this population.

References (32)

  • ER McFadden

    Acute severe asthma

    Am J Respir Crit Care Med

    (2003)
  • M Romagnoli et al.

    Near-fatal asthma phenotype in the ENFUMOSA cohort

    Clin Exp Allergy

    (2007)
  • MC McCormick et al.

    Annual report on access to and utilization of health care for children and youth in the United States: 1999

    Pediatrics

    (2000)
  • CJ DeFrances et al.

    2004 National Hospital Discharge Survey

    Adv Data

    (2006)
  • E Reihsaus et al.

    Mutations in the gene encoding for the β2-adrenergic receptor in normal and asthmatic subjects

    Am J Respir Cell Mol Biol

    (1993)
  • DR Taylor et al.

    Bronchodilator response in relation to β2-adrenoceptor haplotype in patients with asthma

    Am J Respir Crit Care Med

    (2005)

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    This research was supported by the University of Connecticut Health Center General Clinical Research Center (grant M01 RR006192).

    The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

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    Copyright © 2009 The American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.