Characterization of Bronchodilator Response in Children With Bronchiolitis Using Phenotypic and Genotypic Features

Summary

Bronchiolitis is the leading cause of pediatric morbidity and healthcare costs. Despite the commonplace use of bronchodilator treatments, like albuterol, in conditions like asthma, their efficacy in bronchiolitis remains controversial due to the heterogeneity in patient response. Although studies indicate that bronchodilators do not enhance outcomes in bronchiolitis, meta-analyses can obscure the heterogeneity of treatment effects. While bronchodilator response genetics have not been explored in bronchiolitis, treatment effectiveness variations often depend on genomic factors. Genome-wide association studies (GWAS) have linked genetic variants with bronchodilator response and outcomes in childhood asthma, suggesting a bronchodilator-responsive genotype. This proposal aims to extend this paradigm to bronchiolitis, addressing the gap in knowledge where GWAS and clinical characteristics intersect. The proposed study's objective is to characterize phenotypic and genotypic variations of children with bronchiolitis and their association with bronchodilator response. We hypothesize that children with bronchiolitis who exhibit clinical and historical characteristics associated with atopy and specific physical findings have genetic variants linked to bronchodilator response. To achieve this, we propose to (Aim 1) define airway responsiveness to bronchodilator treatment in children with bronchiolitis using the change in respiratory score, (Aim 2a) identify the associations between candidate genetic variants and bronchodilator response among children with bronchiolitis, and (Aim 2b) determine the associations between candidate genetic variants and clinical patient data to identify bronchodilator-responsive children with bronchiolitis. A prospective, double-blind, randomized, placebo-controlled trial of a single albuterol dose in children aged 3 to 24 months presenting with bronchiolitis to the emergency department will be conducted to achieve these aims. Patient information and respiratory assessment outcomes will be collected before and after intervention. Blood, urine, DNA buccal swabs, and nasopharyngeal swabs will also be collected. Completion of these aims will result in a novel clinical prediction model for bronchodilator response determination in bronchiolitis, integrating clinical, physical, and genetic data. Furthermore, this research supports the candidates' career development goals of advancing training in clinical trial research design and execution and becoming an expert in clinical and translational methods to enhance pediatric emergency department health and outcomes. Ultimately, this work will inform an R01 application to validate an evidence-based prediction rule for identifying bronchodilator-responsive children with bronchiolitis through a multi-center emergency medicine research network, optimizing therapeutic approaches, and reducing resource use in those with a low likelihood of bronchodilator response.

Timeline

Start

2022-07-08

Primary completion

2029-12-31

Completion

2030-12-31

Publications

• Background McCulloh RJ, Smitherman SE, Koehn KL, Alverson BK. Assessing the impact of national guidelines on the management of children hospitalized for acute bronchiolitis. Pediatr Pulmonol. 2014 Jul;49(7):688-94. doi: 10.1002/ppul.22835. Epub 2013 Jul 19.
• Background Knapp JF, Simon SD, Sharma V. Variation and trends in ED use of radiographs for asthma, bronchiolitis, and croup in children. Pediatrics. 2013 Aug;132(2):245-52. doi: 10.1542/peds.2012-2830. Epub 2013 Jul 22.
• Background Willson DF, Horn SD, Hendley JO, Smout R, Gassaway J. Effect of practice variation on resource utilization in infants hospitalized for viral lower respiratory illness. Pediatrics. 2001 Oct;108(4):851-5. doi: 10.1542/peds.108.4.851.
• Background Gong C, Byczkowski T, McAneney C, Goyal MK, Florin TA. Emergency Department Management of Bronchiolitis in the United States. Pediatr Emerg Care. 2019 May;35(5):323-329. doi: 10.1097/PEC.0000000000001145.
• Background Viswanathan M, King VJ, Bordley C, Honeycutt AA, Wittenborn J, Jackman AM, Sutton SF, Lohr KN. Management of bronchiolitis in infants and children. Evid Rep Technol Assess (Summ). 2003 Jan;(69):1-5. No abstract available.
• Background Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2014 Jun 17;2014(6):CD001266. doi: 10.1002/14651858.CD001266.pub4.
• Background Ralston SL, Lieberthal AS, Meissner HC, Alverson BK, Baley JE, Gadomski AM, Johnson DW, Light MJ, Maraqa NF, Mendonca EA, Phelan KJ, Zorc JJ, Stanko-Lopp D, Brown MA, Nathanson I, Rosenblum E, Sayles S 3rd, Hernandez-Cancio S; American Academy of Pediatrics. Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014 Nov;134(5):e1474-502. doi: 10.1542/peds.2014-2742.
• Background Pelletier AJ, Mansbach JM, Camargo CA Jr. Direct medical costs of bronchiolitis hospitalizations in the United States. Pediatrics. 2006 Dec;118(6):2418-23. doi: 10.1542/peds.2006-1193.
• Background Hasegawa K, Tsugawa Y, Brown DF, Mansbach JM, Camargo CA Jr. Trends in bronchiolitis hospitalizations in the United States, 2000-2009. Pediatrics. 2013 Jul;132(1):28-36. doi: 10.1542/peds.2012-3877. Epub 2013 Jun 3.
• Background Willer RJ, Coon ER, Harrison WN, Ralston SL. Trends in Hospital Costs and Levels of Services Provided for Children With Bronchiolitis Treated in Children's Hospitals. JAMA Netw Open. 2021 Oct 1;4(10):e2129920. doi: 10.1001/jamanetworkopen.2021.29920.
• Background Keren R, Luan X, Localio R, Hall M, McLeod L, Dai D, Srivastava R; Pediatric Research in Inpatient Settings (PRIS) Network. Prioritization of comparative effectiveness research topics in hospital pediatrics. Arch Pediatr Adolesc Med. 2012 Dec;166(12):1155-64. doi: 10.1001/archpediatrics.2012.1266.
• Background Meissner HC. Viral Bronchiolitis in Children. N Engl J Med. 2016 Jan 7;374(1):62-72. doi: 10.1056/NEJMra1413456. No abstract available.
• Background Fujiogi M, Goto T, Yasunaga H, Fujishiro J, Mansbach JM, Camargo CA Jr, Hasegawa K. Trends in Bronchiolitis Hospitalizations in the United States: 2000-2016. Pediatrics. 2019 Dec;144(6):e20192614. doi: 10.1542/peds.2019-2614. Epub 2019 Nov 7.

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