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

Abstract

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 microg twice daily (FP monotherapy), combination fluticasone 100 microg 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 < or = .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, beta-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.

Figure 1

Number of participants in the Pediatric Asthma Controller Trial with no, one, two, three exacerbations in each treatment group. 48% had at least one exacerbation and 22% had more than one exacerbation: Fewer participants in the FP monotherapy group developed an asthma exacerbation during the trial, compared to those who were treated with montelukast (p=0.009 FP monotherapy vs montelukast, p=0.09 FP monotherapy vs PACT combination, p=0.2 PACT combination vs montelukast).

Figure 2

Number of exacerbations in the winter (Dec–Feb), spring (Mar–May), summer (June–Aug), and fall (Sept–Nov) months Exacerbations were more likely to occur in the spring (p<0.001) or winter (p=0.001) or fall (p<0.0001) compared to the summer months.

Figure 3

Plots of cough/wheeze severity score (scale 0–3), rescue albuterol rescue use (# inhalations per day), and AM PEF as % predicted of participants in the montelukast, PACT combination, and FP monotherapy groups, relative to an exacerbation.