Effectiveness of elexacaftor/tezacaftor/ivacaftor therapy in children and adolescents with cystic fibrosis and normal spirometry

Background: Cystic fibrosis (CF) is a genetic disorder caused by variants in the CFTR gene. CFTR modulators, especially elexacaftor/tezacaftor/ivacaftor (ETI), have significantly improved CF care, but their effectiveness in children and adolescents with normal spirometry remains unexplored. Methods: This prospective study included 103 individuals with CF under 18 years old, all with baseline percent predicted forced expiratory volume in one second (ppFEV1) ≥ 90%. The outcomes assessed included sweat chloride concentration (SCC), body mass index (BMI), forced expiratory volume in one second (ppFEV1), lung clearance index (LCI2.5), P. aeruginosa colonization, and pulmonary exacerbation (PEX) rates over 12 months. Results: Despite normal spirometry at baseline, 73.5% of participants exhibited abnormal LCI2.5, indicating early lung disease. After ETI therapy, significant improvements were observed: SCC decreased by 56.0 mmol/L (95% CI: -60.6, -51.4) at 12 months; BMI increased by 0.26 standard deviation scores (95% CI: 0.18, 0.33); ppFEV1 improved by 8.3 points (95% CI: 6.6, 10.1); and LCI2.5 decreased by 1.68 units (95% CI: -2.00, -1.37). Additionally, the annual PEX rate declined from 2.75 to 1.50 (rate ratio: 0.54, 95% CI: 0.45-0.66). Conclusions: ETI therapy provided substantial clinical benefits, supporting early intervention in pediatric patients with CF, even with preserved spirometry. Impact: This study explored the effects of ETI therapy in children and adolescents with CF and normal spirometry. Most showed early signs of lung disease based on LCI evaluation. ETI led to significant improvements in lung function and growth. Our findings stress the importance of early ETI intervention to optimize both growth and lung health in patients with CF.