Effective Treatments Highlighted for Children with Uncontrolled Asthma on Corticosteroids

A medium-dose inhaled corticosteroid along with a long-acting β2-agonist have been recommended in a new analysis for children with uncontrolled asthma on inhaled corticosteroid alone, and investigators urge against use of a leukotriene receptor antagonist alone.1

These data resulted from a recent analysis conducted to assess the clinical efficacu of different pharmacological treatments among pediatric patients with uncontrolled asthma on inhaled corticosteroid. The investigative team sought to examine cost-effectiveness and to identify and assess the potential for treatment effect modification, with the larger aim being treatment delivery optimization.

The investigators were led by Sofia Cividini, MD, MSc, from the Department of Health Data Science (HDS) at the UK’s University of Liverpool. Cividini and coauthors noted that before this analysis, there had been a lack of a clear preferential option for the initial step-up of children’s treatment for uncontrolled asthma on an inhaled corticosteroid.

A systematic review and network meta-analysis was conducted by Cividini et al, with individual participant data drawn from randomized controlled trials (both parallel and crossover designs) being used. These trials had included individuals under the age of 18 years with uncontrolled asthma who were also being given any dose of inhaled corticosteroids (ICS) as a monotherapy.

The investigative team's search strategy involved multiple sources—MEDLINE, the Cochrane Library, the Cochrane Central Register of Controlled Trials, EMBASE, NICE Technology Appraisals, and the NIHR Health Technology Assessment series. Eligible research included in the investigators' analysis compared at least a single pharmacological intervention of note.

The main outcomes evaluated by the team were asthma exacerbations and asthma control, and they determined that secondary outcomes would include mortality, health-related quality of life, forced expiratory volume in a single second (FEV₁), hospital admissions, and adverse events (AEs). The Cochrane Risk of Bias tool was implemented by Cividini and colleagues to evaluate the quality of these studies.

Statistical analyses employed Bayesian methods for the purposes of pairwise and network meta-analyses, along with meta-regression for evaluations of potential interactions between treatment effects and covariates. Covariates included sex, age, ethnicity, eosinophilia, eczema, and asthma severity among patients.

There were 4,708 records screened in total and 144 randomized trials deemed eligible for inclusion by the investigative team. Among the studies' subjects, collection of individual participant data was carried out from 29 analyses, encompassing 5,381 participants. The team extracted limited aggregate data from 19 other studies.

Most of the studies included in Cividini et al's analysis showed a low risk of bias. The investigators' network meta-analysis suggested that medium-dose ICS therapy provided along with a long-acting β2-agonist (LABA) had significantly diminished patients' odds of asthma exacerbations versus low-dose ICS by itself, with an odds ratio of 0.43 (95% CI: 0.20 - 0.92). This was based on 40 studies involving 8,168 inviduals.

This specific combination also led to notable FEV₁ improvements among trial subjects compared to low-dose ICS, with a mean difference of 0.71 (95% CI: 0.35 to 1.06; 23 studies, 2,518 individuals). Conversely, Cividini and coauthors found that monotherapy using a leukotriene receptor antagonist (LTRA) was shown to be the least effective option for patients across these outcomes.

Additionally, the investigators did not identify any significant differences in asthma control between treatment cohorts (16 studies, 3,027 individuals). They also highlighted limited pairwise data pointing to a possible benefit in health-related quality of life of patients favoring medium-dose ICS alone compared to ICS combined with LABA, with a mean difference of 0.91 (95% CI: 0.29 - 1.53). This was based on the pediatric asthma quality of life questionnaire from 2 specific studies.

Cividini and colleagues highlighted variation in hospitalization rates due to asthma attacks, ranging from 0.5% - 2.7% across 5 studies. In their evaluation of safety findings, the investigators found fewer reports of neurological AEs (mild or moderate) among participants on ICS + LABA compared to participants on ICS + LTRA, with an odds ratio of 0.09 (95% CI: 0.01 - 0.82; one study).

No instances of death were reported across the included studies and there was no robust or consistent evidence to indicate that demographic or clinical factors modified the treatments' effects. The team also carried out an economic analysis, implementing a Markov decision model with a 1-year horizon from the perspective of the UK National Health Service and Personal Social Services.

Cost-effectiveness was expressed as incremental cost per quality-adjusted life year (QALY) gained, with 1-way, structural, and probabilistic sensitivity analyses being used. Cividini et al suggested that although low-dose ICS was the most cost-effective strategy, medium-dose ICS—either alone or in combination with LABA—was linked to the greatest QALY gains among patients.

Despite this finding, the investigators further noted that the incremental cost-effectiveness ratios for these higher-intensity treatments exceeded the cost-effectiveness threshold set by NICE.

“Medium-dose inhaled corticosteroid + long-acting β2-agonist is recommended for children with asthma that is uncontrolled on inhaled corticosteroid alone; leukotriene receptor antagonist alone should be avoided,” the investigators concluded.1 “We could not include data from 67% of the eligible trials, conclusions should therefore be viewed with some caution.”

References

1. Cividini S, Sinha I, Smith CT, et al; Establishing the best step-up treatments for children with uncontrolled asthma despite inhaled corticosteroids: the EINSTEIN systematic review, network meta-analysis and cost-effectiveness analysis using individual participant data. Health Technol Assess. 2025 May;29(15):1-234. doi: 10.3310/HGWT3617. PMID: 40383994; PMCID: PMC12104851.

2. Lemanske RF Jr, Mauger DT, Martinez FD, et al. Childhood Asthma Research and Education (CARE) Network of the National Heart, Lung, and Blood Institute. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010;362:975–85. doi: 10.1056/NEJMoa1001278.