Factors associated with asthma exacerbations during a long-term clinical trial of controller medications in children

doi:10.1016/j.jaci.2008.08.021

Journal of Allergy and Clinical Immunology

Volume 122, Issue 4, October 2008, Pages 741-747.e4

https://doi.org/10.1016/j.jaci.2008.08.021 Get rights and content

Background

Asthma exacerbations are a common cause of critical illness in children.

Objective

To determine factors associated with exacerbations in children with persistent asthma.

Methods

Regression modeling was used to identify historical, phenotypic, treatment, and time-dependent factors associated with the occurrence of exacerbations, defined by need for oral corticosteroids or emergency or hospital care in the 48-week Pediatric Asthma Controller Trial study. Children age 6 to 14 years with mild-to-moderate persistent asthma were randomized to receive either fluticasone propionate 100 μg twice daily (FP monotherapy), combination fluticasone 100 μg AM and salmeterol twice daily, or montelukast 5 mg once daily.

Results

Of the 285 participants randomized, 48% had 231 exacerbations. Using a multivariate analysis, which included numerous demographic, pulmonary, and inflammatory parameters, only a history of an asthma exacerbation requiring a systemic corticosteroid in the past year (odds ratio [OR], 2.10; P < .001) was associated with a subsequent exacerbation during the trial. During the trial, treatment with montelukast versus FP monotherapy (OR, 2.00; P = .005), season (spring, fall, or winter vs summer; P ≤ .001), and average seasonal 5% reduction in AM peak expiratory flow (OR, 1.21; P = .01) were each associated with exacerbations. Changes in worsening of symptoms, β-agonist use, and low peak expiratory flow track together before an exacerbation, but have poor positive predictive value of exacerbation.

Conclusion

Children with mild-to-moderate persistent asthma with previous exacerbations are more likely to have a repeat exacerbation despite controller treatment. Inhaled corticosteroids are superior to montelukast at modifying the exacerbation risk. Available physiologic measures and biomarkers and diary card tracking are not reliable predictors of asthma exacerbations.

Section snippets

Methods

Details of the PACT study and its procedures have been reported⁴ and are briefly summarized. PACT was a multicenter 48-week randomized, double-blind, placebo-controlled, double-dummy, parallel-group study of 285 children 6 to 14 years of age with documented mild-moderate persistent asthma, screening FEV₁ ≥80% predicted, and methacholine reactivity. Treatments compared were fluticasone propionate 100 μg twice daily (FP monotherapy), FP 100 μg/salmeterol 50 μg in the morning and salmeterol 50 μg

Results

A total of 231 asthma exacerbations occurred in 48% of the participants during the course of the treatment phase. Twenty-two percent (n = 64) had 2 or more exacerbations (Fig 1). Of the exacerbations, 74 (53%), 35 (26%), and 29 (21%) were first, second, and third exacerbations, respectively. The mean ± SD (median) time to the first exacerbation was 127 ± 103 (99) days.

Discussion

Our analysis of asthma exacerbations of children with mild-to-moderate asthma enrolled in the 1-year multicenter PACT study using an extensive panel of physiologic and biologic markers revealed important features associated with the occurrence of an exacerbation.

Host and environmental factors that increase the risk of asthma exacerbations in children and those that could be targeted by interventions are not well defined. Of the numerous baseline historical, phenotypic, and immunologic and

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: Supported by grants 5U10HL064287, 5U10HL064288, 5U10HL064295, 5U10HL064307, 5U10HL064305, and 5U10HL064313 from the National Heart, Lung, and Blood Institute; General Clinical Research Centers at Washington University School of Medicine (M01 RR00036); and National Jewish Medical and Research Center (M01 RR00051).

: Disclosure of potential conflict of interest: R. A. Covar has received honoraria from Aerocrine NIOX and has received research support as a coinvestigator from Abbott Laboratories. S. J. Szefler has served as a consultant for AstraZeneca, GlaxoSmithKline, Aventis, Genentech, and Merck and has received research grants from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) Childhood Asthma Management Program, NHLBI Childhood Asthma Research and Education, the NIH/NHLBI Asthma Clin Res Network, the NIH/National Institute of Allergy and Infectious Diseases Inner-City Asthma Consortium, and Ross Pharmaceuticals. R. S. Zeiger has served as a consultant for Aerocrine, AstraZeneca, Dynavax, Genentech, Merck, Novartis, and GlaxoSmithKline and has received research support from Sanofi-Aventis, Teva-Pharmaceuticals, Merck, AstraZeneca, GlaxoSmithKline, and Genentech. C. A. Sorkness has served on the speakers' bureau for GlaxoSmithKline and has received research support from GlaxoSmithKline and Pharmaxis. The rest of the authors have declared that they have no conflict of interest.

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Asthma and lower airway diseaseFactors associated with asthma exacerbations during a long-term clinical trial of controller medications in children

Background

Objective

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Pediatr

Ann Emerg Med

Chest

Long-term effects of budesonide or nedocromil in children with asthma. Childhood Asthma Management Program Research Group

N Engl J Med

Computer-based models to identify high-risk children with asthma

Am J Respir Crit Care Med

Asthma and lower airway disease
Factors associated with asthma exacerbations during a long-term clinical trial of controller medications in children