PURPOSE OF THE STUDY.
To determine if a differential response to asthma controller medications exists among young children with a history of wheezing requiring step 2 therapy and if this response can be predicted by phenotype and clinically available biomarkers.
Enrolled subjects were 300 children aged 12 to 59 months who required step 2 asthma therapy, including those who were naive to inhaled corticosteroids (ICSs) and leukotriene receptor antagonist (LTRA) medications and those who had been treated with low-dose ICSs or LTRAs at any point in the 6 months before enrollment but still experiencing symptoms warranting daily controller medication.
This study was a multicenter, randomized, double-blind, double-dummy clinical trial. A run-in period of 2 to 8 weeks, depending on history of previous exacerbation requiring systemic corticosteroids and on current usage of step 2 therapy, was used to assess asthma severity and control. Treatment occurred over 48 weeks as three 16-week treatment arms via randomized, placebo-controlled crossover including: daily ICSs (fluticasone 44 mcg, 2 inhalations twice daily), daily LTRAs (4 mg at bedtime), and as-needed ICSs (fluticasone 44 mcg, 2 inhalations) co-administered with open-label, short-acting bronchodilator (90 mcg, 2 inhalations). No washout period was performed; however, the first 2 weeks of data were not analyzed in calculation of asthma control days (ACDs). Caregivers recorded symptoms, health care use, and medication use in electronic diaries at bedtime. Biomarkers included aeroallergen sensitization and blood eosinophil counts. Primary analysis was based on determination of differential response and 3 prespecified factors (aeroallergen sensitization, previous exacerbation, and sex).
Of those enrolled, 230 had analyzable data; 74% (170/230) of subjects were differential responders to treatment (defined as time to asthma exacerbation at least 4 weeks longer or number of annualized ACDs at least 31 days more compared with another treatment), with the highest probability of best response being daily ICSs (P < .0001) associated with greater ACDs and less exacerbations. Aeroallergen sensitization (P = .0036), blood eosinophil counts of 300 µL or greater (P = .0071), and serum eosinophilic cationic protein of 10 µg/l or greater (P = .0292) were associated with differential response favoring daily ICSs. However, previous exacerbation history, sex, modified asthma predictive index status, serum immunoglobulin E (IgE) levels, and urinary leukotriene E4 (LTE4) concentrations were not predictive of differential response.
This study shows that daily ICSs conferred the most protection against symptoms and exacerbations in children with type 2 inflammation evidenced by aeroallergen sensitization and increased blood eosinophil counts. Moreover, clinically accessible biomarkers can be used to predict the medication strategy associated with best response.
This study demonstrates that phenotype-directed daily ICSs is beneficial in children with type 2 inflammation, even though the risk of dose-dependent reductions in linear growth with daily ICSs may be worse in certain subpopulations. However, more studies need to be done on children who show nontype 2 patterns of inflammation, as these children may have unique inflammatory profiles which may guide treatment selection.
- Copyright © 2017 by the American Academy of Pediatrics