Rate of Lung Function Decline in People with Cystic Fibrosis Having a Residual Function Gene Mutation

Abstract

Introduction: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approximately 5% of people with CF have residual function (RF) CFTR mutations that result in partially retained CFTR activity. Published literature on disease trajectory among those with RF mutations is limited. In this retrospective study, we characterized lung function decline across different age groups in CFTR modulator-untreated people with CF heterozygous for F508del and an RF mutation (F/RF). Methods: Rate of decline in percent predicted forced expiratory volume in 1 s (ppFEV1) was analyzed using data from the US CF Foundation Patient Registry (2006–2014) in F/RF (all), F/RF (excluding R117H), and F508del homozygous (F/F) cohorts. Annual rates of ppFEV1 decline were estimated over 2-year periods based on calendar year. Subgroup analyses by age [6–12 (children), 13–17 (adolescents), 18–24 (young adults), and ≥ 25 years (adults)] were performed. Results: The estimated annualized rate of ppFEV1 decline was − 0.70 percentage points per year (95% CI −1.09, −0.30) in the F/RF (all) cohort (N = 1242) versus −1.91 percentage points per year (95% CI −2.01, −1.80) in the F/F cohort (N = 11,916) [difference, 1.29 percentage points per year (95% CI 0.88, 1.70); P < 0.001]. In the F/RF (all) cohort, all age groups demonstrated lung function decline ranging from −0.30 to −1.38. In the F/RF (excluding R117H) cohort, the rate of decline was −1.05 percentage points per year (95% CI −1.51, −0.60) [difference versus F/F cohort, 0.95 percentage points per year (95% CI 0.48, 1.41; P < 0.001); not statistically significant in children and young adults]. Conclusion: Progressive lung function decline was observed in people with F/RF genotypes across all assessed age groups, reinforcing the importance of early intervention and clinical monitoring to preserve lung function in all people with CF.