Biomarkers to Predict Response to ICS and LAMA in Adolescents and Adults with Mild Persistent Asthma.

Rationale Whether biomarkers can be used to predict response to inhaled corticosteroids (ICS) or long-acting muscarinic antagonists (LAMA) in mild persistent asthma is unclear. Objectives In a pre-specified exploratory analysis of a randomized clinical trial of 295 participants >12 years old with uncontrolled mild persistent asthma, we sought to identify biomarkers of treatment response after 12 weeks of ICS (mometasone 200µg or 220µg twice/day), LAMA (tiotropium 5µg/day), or placebo in adults (>18 years) and adolescents (12-17 years) separately. Methods The primary outcome was a composite outcome of asthma control (treatment failure, asthma control days, and forced expired volume in the first second [FEV1]). Analyses examined Type 2 inflammatory biomarkers and physiologic biomarkers. We assessed the area under curve (AUC) for response to ICS and LAMA (each vs. placebo). An AUC of 0.5 suggests no discrimination, 0.7 to 0.8 is considered acceptable, more than 0.8 to 0.9 is considered excellent, and more than 0.9 is considered outstanding. Results In 237 adults, sputum and blood eosinophil levels and FeNO each predicted ICS response (AUCs 0.61 (95% confidence interval [CI], 0.53-0.69), 0.64 (95% CI, 0.56-0.72), and 0.62 (95% CI, 0.54-0.70), respectively; all p-values<0.01); the AUC for blood eosinophil levels and FeNO together = 0.66 (95% CI, 0.58-0.74), p<0.001. In 58 adolescents, the number of positive aeroallergens and total serum IgE each predicted ICS response (AUCs 0.69 (95% CI, 0.52-0.85) and 0.73 (95% CI, 0.58-0.87), respectively; both p-values<0.03); the AUC for both together was 0.73 (95% CI, 0.58-0.87), p=0.003. Post-ipratropium bromide FEV1 reversibility predicted LAMA response in adults (AUC 0.61 (95% CI, 0.53-0.69), p=0.007), but not in adolescents. Conclusions The AUCs of the Type 2 inflammatory biomarkers and physiologic biomarkers we examined may not be high enough to confidently identify individuals with asthma who respond to ICS and LAMA. However, our findings indicate that the biomarkers that predict response to ICS or LAMA may differ in adults versus adolescents with uncontrolled mild persistent asthma. Prospective, biomarker-stratified clinical trials are needed to confirm these findings and to identify first-line controllers tailored for each population. Clinical trial registered with ClinicalTrials.gov (NCT02066298).