Context

Asthma is the commonest chronic illness of childhood.1 As prevention is impossible, management is aimed at controlling symptoms and reducing future risk. Although inhaled corticosteroids (ICS) are highly effective in controlling asthma, some children will continue to have symptoms or exacerbations2 and may require more treatment. The principal ‘step-up’ options include adding either an inhaled long-acting β-agonist (LABA) or an oral leukotriene receptor antagonist (LTRA) to ICS or using high-dose ICS. The evidence base informing this decision is weak in children, and controversy persists.3 Guidelines suggest that for children aged 5 years or older, LABA addition is the best ‘first-choice’ option,1 although recent safely concerns have lead the FDA to make different recommendations.4 This timely study aimed to compare the efficiency of these three step-up options in children who remained symptomatic despite ICS (fluticasone 100 μg twice daily). It also aimed to identify phenotypic or genotypic factors predicting a differential response to treatment.

Findings

Retention was good, with 161 out of 182 randomised participants providing data. Adherence to medication was high (84% for tablets and 87% for inhalers). A differential response occurred in 98% of participants. LABA was associated with the greatest chance of a better response, although marked heterogeneity was seen. Overall, 43% responded best to LABA, 29% to LTRA and 26% to high-dose ICS. In pairwise comparisons, a higher proportion had a better response to LABA than to LTRA (52% vs 34%, p=0.02) and a better response to LABA than to high-dose ICS (54% vs 32%, p=0.004), without significant differences between LTRA and high-dose ICS.

A variety of preselected and posthoc factors were assessed as markers of differential response, but most were unhelpful, including the fraction of exhaled nitric oxide, methacholine PC20, bronchodilator reversibility, β-2 adrenoreceptor genotype, age, sex, allergic sensitisation and baseline exacerbation frequency. Better baseline symptom scores predicted a greater probability of LABA success. Hispanic and non-Hispanic white patients were most likely to have a better response to LABA and least likely to ICS; black children were equally likely to have a best response of LABA or ICS and least to LTRA. Children without eczema were more likely to have a best response to LABA.

Commentary

This was a well-designed and well-executed study. Although baseline characteristics appear to indicate a representative US demographic profile, the high compliance levels to medication and protocol may indicate an atypically ‘well-behaved’ group. As non-adherence is commonly seen in ‘real-word’ settings and may be more common with inhaled than oral therapies, some caution is needed in extrapolation.

The heterogeneity of response seen is remarkable and illustrates the complexity of asthma. It is unlikely that a ‘one size fits all’ approach is going to provide the best outcomes in asthma, and close monitoring of patients and willingness to try different therapies may be needed. Guidelines can advise on the best first-choice therapeutic option, but can't predict the most effective treatment for the individual. It is disappointing that markers for differential responses proved so hard to find. The baseline measurements were made after run-in on regular ICS, which could have affected signals. This study was focused on short-term effectiveness. It was neither designed nor powered to look at long-term control or safety aspects of these therapies, issues that will continue to affect decision making.

The study confirms the heterogeneity of childhood asthma; although LABA step-up was most likely to be most effective, many children had a better response to high-dose ICS or to LTRA. All children undergoing step-up need close monitoring and may require subsequent therapy adjustment.