Predictors of asthma control and lung function responsiveness to step 3 therapy in children with uncontrolled asthma

Abstract

Background Predictors of improvement in asthma control and lung function to STEP-3 therapy in children with persistent asthma have not been identified despite reported heterogeneity in responsiveness. Objective To evaluate potential predictors of asthma control and lung function responsiveness to STEP-3 therapy. Methods A post-hoc analysis from the Best Add-On Giving Effective Response (BADGER) study tested the association between baseline biological, asthma control, pulmonary function and demographic markers and responsiveness to step-up to higher dose inhaled corticosteroids (ICS step-up), or addition of leukotriene receptor antagonist (LTRA step-up) or long acting beta-2 (LABA step-up) therapy. Results In multivariate analyses, higher impulse oscillometry (IOS) AX levels were associated (p=0.047) with a differential forced expiratory volume in 1-second (FEV1) response favoring LABA over ICS step-up while higher levels of urinary leukotriene E4 (uLTE4) were marginally (p=0.053) related to a differential FEV1 response favoring LTRA over LABA step-up therapy. Predictors of differential responses comparing ICS to LTRA step-up therapy were not apparent probably due to suppression of allergic markers with low-dose ICS treatment. Minimal overlap was seen across FEV1 and asthma control day (ACD) predictors suggesting distinct mechanisms related to lung function and ACD responses. Conclusion Levels of IOS AX indicating peripheral airway obstruction and uLTE4 indicating cysteinyl leukotriene inflammation can differentiate LABA step-up responses from responses to LTRA or ICS step-up. Further studies with physiological, genetic and biological markers related to these phenotypes will be needed to predict individual responses to LABA step-up therapy.

Roflumilast combined with montelukast versus montelukast alone as add-on treatment in patients with moderate-to-severe asthma

“…For example, in children with uncontrolled asthma receiving step 3 treatment, an increased LTE 4 /FENO ratio predicts a more favorable response to montelukast. 26 In the current study it is of interest that urinary LTE 4 baseline levels were high in spite of current ICS use, suggesting that the patients in this study were relatively refractory to ICSs. ICSs have been shown to reduce urinary LTE 4 levels.…”

“…ICSs have been shown to reduce urinary LTE 4 levels. 26 Surprisingly, montelukast alone also seemed ineffective in reducing urinary LTE 4 levels, and if anything, levels increased during montelukast treatment and only decreased when roflumilast was added. No changes in numbers of circulating neutrophils, eosinophils, or other leukocytes were noted during the study, and no other significant trends in inflammatory markers were evident.…”

Individualized Therapy for Persistent Asthma in Young Children

“…Exploratory analyses utilized rank-ordered logistic regression to examine other phenotypic characteristics that might predict patterns of treatment response. Pre-specified exploratory analyses focused on serum eosinophil cationic protein (ECP) levels 21 and urinary leukotriene E 4 (LTE 4 ) concentrations 26 as predictors of treatment response. Blood eosinophils, specific aeroallergen tests results, serum IgE and modified Asthma Predictive Index 27 (mAPI) status, defined by a history of 4 or more wheezing episodes plus one major criteria (parental history of asthma, physician-diagnosed atopic dermatitis, or allergic sensitization to ≥1 aeroallergen) or two minor criteria (allergic sensitization to milk, egg, or peanut, wheezing unrelated to colds, or blood eosinophils ≥4%), 28 were examined post-hoc as potential predictors.…”

Advances in pediatric asthma in 2014: Moving toward a population health perspective

“…Rabinovitch et al 94 evaluated potential predictors of asthma control and lung function responsiveness to step 3 therapy and noted that available measures, such as measurement of exhaled nitric oxide and even leukotriene E 4 , do not reliably predict response to step 3 therapy. 94 An analysis of the same study by Malka et al 95 reported that race/ethnicity along with eczema history could be associated with differential response to long-acting b-adrenergic agonist (LABA), increased ICS, and leukotriene receptor antagonist (LTRA) step-up therapy. LABA step-up therapy is the preferred step-up treatment in asthmatic children without eczema.…”