Individualized therapy for persistent asthma in young children

Abstract

Background: Phenotypic presentations in young children with asthma are varied and might contribute to differential responses to asthma controller medications.

Methods: The Individualized Therapy for Asthma in Toddlers study was a multicenter, randomized, double-blind, double-dummy clinical trial in children aged 12 to 59 months (n = 300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2- to 8-week run-in period followed by 3 crossover periods with daily inhaled corticosteroids (ICSs), daily leukotriene receptor antagonists, and as-needed ICS treatment coadministered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved 2 stages: determination of differential response and assessment of whether 3 prespecified features (aeroallergen sensitization, previous exacerbations, and sex) predicted a differential response.

Results: Seventy-four percent (170/230) of children with analyzable data had a differential response to the 3 treatment strategies. Within differential responders, the probability of best response was highest for a daily ICS and was predicted by aeroallergen sensitization but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophil counts of 300/μL or greater. In these children daily ICS use was associated with more asthma control days and fewer exacerbations compared with the other treatments.

Conclusions: In young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophil counts is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with a daily ICS is beneficial despite possible risks of growth suppression.

Trial registration: ClinicalTrials.gov NCT01606306.

Keywords: Asthma; asthma biomarkers; asthma phenotype; asthma treatment; inhaled corticosteroid; leukotriene receptor antagonist; personalized medicine; treatment response.

Figure 1

Study diagram and procedures. ICS = inhaled corticosteroid; LTRA = leukotriene receptor antagonist; Diary = electronic diary distribution and data review; Height = height measurement, Blood = blood collection; Urine = urine collection. The “+” sign indicates that the procedure was performed.

Figure 2

Flow chart depicting the number of participants who enrolled in the study, underwent randomization, and completed the study, and provided analyzable data for analysis.

Figure 3

(A) Probability of each asthma treatment being the best of the three. Gray shading depicts participants who did not have a differential response. (B) The percentage of Asthma Control Days (ACDs) and (C) the probability of an exacerbation.. Boxplots represent the median value, 25^th to 75^th percentile (shading) and 5^th to 95^th percentile (whiskers). Outliers are shown as triangles.

Figure 4

The probability of best response based on (A) aeroallergen sensitization, (B) previous exacerbation, (C) sex, (D) eosinophils ≥300/μL, and (E) combinations of sensitization and eosinophils. P-values correspond to the test of interaction between the predictor and treatment and indicate whether the pattern of treatment response differs according to subgroup. Sample sizes correspond to participants with evaluable data (N = 230).

Figure 5

The cumulative probability of an exacerbation requiring systemic corticosteroids for all participants with evaluable data (N = 230), stratified by (A) aeroallergen sensitization, (B) blood eosinophils ≥300/μL, and (C) combinations of aeroallergen sensitization and blood eosinophils.