ADRB2 genotype-guided treatment for childhood asthma: an individual patient data meta-analysis of the PACT and PUFFIN trial

<bold>Background:</bold> Long-acting β2-agonists (LABA) are commonly used to treat asthma, however, some children do not respond to LABA. This might be due to variation in the A allele of rs1042713 (Arg16 amino acid) in the ADRB2 gene encoding the β2 receptor. We investigated whether Arg16Gly genotype-guided treatment improved asthma-related outcomes. <bold>Methods:</bold> We recruited Dutch and Swiss 6-18-year-old (PUFFIN) and 12-18-year-old children from England and Scotland (PACT) with uncontrolled asthma despite inhaled corticosteroids (ICS) and performed an individual patient data meta-analysis of the two randomised controlled trials. Patients requiring step-up were randomised to genotype-guided treatment (adding LABA (Gly16Gly) or montelukast (PACT)/a double dose of ICS (PUFFIN) (Arg16Arg/Arg16Gly)) or standard care with a follow-up of at least 6 months. The primary outcome was change in asthma control. Secondary outcomes were change in exacerbation rate and time to exacerbation. Repeated measures mixed models (RMMM) and cox regression were used. Due to missing data, PACT baseline exacerbations were coded as 0, no exacerbations. <bold>Results:</bold> 59 out of 102 (PUFFIN) and 59 out of 91 (PACT) children had at least one A allele. These 193 children were included. There was no difference in asthma control between both arms during follow-up. Genotype-guided treatment resulted in lower asthma exacerbation rates (−0.080 (−0.155 - -0.004, p=0.038)) and a trend towards longer time to exacerbation (HR 0.66 (95%CI 0.41-1.06, p=0.085)) compared to standard care. <bold>Conclusion:</bold> Genotype-guided step-up treatment for children with uncontrolled asthma on ICS may lower asthma exacerbation rates.