Predictors of poor response during asthma therapy differ with definition of outcome

Abstract

Aims: To evaluate phenotypic and genetic variables associated with a poor long-term response to inhaled corticosteroid therapy for asthma, based independently on lung function changes or asthma exacerbations.

Materials & methods: We tested 17 phenotypic variables and polymorphisms in FCER2 and CRHR1 in 311 children (aged 5-12 years) randomized to a 4-year course of inhaled corticosteroid during the Childhood Asthma Management Program (CAMP).

Results: Predictors of recurrent asthma exacerbations are distinct from predictors of poor lung function response. A history of prior asthma exacerbations, younger age and a higher IgE level (p < 0.05) are associated with recurrent exacerbations. By contrast, lower bronchodilator response to albuterol and the minor alleles of RS242941 in CRHR1 and T2206C in FCER2 (p < 0.05) are associated with poor lung function response. Poor lung function response does not increase the risk of exacerbations and vice versa (p = 0.72).

Conclusion: Genetic and phenotypic predictors of a poor long-term response to inhaled corticosteroids differ markedly depending on definition of outcome (based on exacerbations vs lung function). These findings are important in comparing outcomes of clinical trials and in designing future pharmacogenetic studies.

Figure 1. Number of exacerbations among rare versus recurrent exacerbators in response to inhaled corticosteroid in The Childhood Asthma Management Program

Recurrent exacerbators are those with two or more exacerbations in both years 1–2 and years 3–4 (n = 66). Rare exacerbators had at most one exacerbation over the 4-year trial period (n = 136). Subjects with two to three exacerbations (n = 68), missing follow-up visits for at least 1 year (n = 10) and those with greater than or equal to four exacerbations but only during one 2-year period (n = 31) were excluded from analysis.

Figure 2. Change in percentage of predicted FEV1 from baseline at four representative follow-up visits

FEV₁ response to inhaled corticosteroids demonstrates substantial variability at each measured time point. FEV₁: Forced expiratory volume in 1 second.

Figure 3. Proportion of rare and recurrent exacerbators with poor lung function response

Of the 131 rare exacerbators, 22% had a poor FEV₁ response (never improved by 7.5% during follow-up); similarly, of the 63 recurrent exacerbators, 25% had a poor FEV₁ response (Fisher’s exact p-value = 0.72). The proportion of nonresponders is similar, suggesting that these are independent phenotypes. FEV₁: Forced expiratory volume in 1 second.