Beyond the Lung. Impact of Elexacaftor/Tezacaftor/Ivacaftor on Sinonasal Disease in Children With Cystic Fibrosis

Abstract

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) therapy that improves pulmonary function and chronic rhinosinusitis (CRS) in cystic fibrosis (CF) adults with at least one copy of the F508del CFTR mutation. The purpose of this study is to evaluate the impact of ETI on CRS symptoms in children and adolescents with CF.

Methods: The MODUL-CF observational study is a multicenter prospective cohort study enrolling CF children with at least 1 F508del mutation in France. Subjects answered a standardized questionnaire on nasal obstruction and smell and were invited to complete the Sinus and Nasal Quality of Life Survey (SN-5) questionnaire prior to ETI therapy and at 1, 3, 6, and 12 months ETI. Part of the cohort underwent sinus computerized tomography (CT) within an ancillary study, scored by the Lund-Mackay CT score (LMKS).

Results: Of 391 subjects, 94 (24.0%) were aged between 6 and 12 years, and 297 were adolescents. Sixty-four (16.3%) reported nasal obstruction at baseline. One hundred and sixty-three completed the SN-5 questionnaire at M0, 181 at M12, and 123 at M0 and M12. Mean SN-5 global score baseline value was similar to that of a healthy pediatric control cohort. SN-5 global score, nasal obstruction, sinus infection, and emotion domain subscores improved significantly at 1 month and this was sustained over 12 months. LMKS improved significantly in 43 patients who underwent sinus CT at M0 and M12.

Conclusion: ETI improves sinonasal symptoms and related quality of life (QOL), including emotion domain, in children and adolescents with CF.

Keywords: CFTR; CFTR modulators; chronic rhinosinusitis; cystic fibrosis; quality of life.

FIGURE 1

Evolution of nasal obstruction. Number of patients reporting nasal obstruction at baseline (M0) and follow‐up visits (M1, M3, M6, M12) in all the patients, the 6–12‐year‐old children and the 13–17‐year‐old adolescents. Trend test is shown. p‐values are derived from generalized linear mixed‐effects models for repeated measures (MMRM) with time as a continuous covariate.

FIGURE 2

Evolution of the SN‐5 score over time according to baseline nasal obstruction. Mean SN‐5 score at baseline (M0) and follow‐up visits (M1, M3, M6, M12). Data shown as mean and standard error.

FIGURE 3

Percentage of patients according to answers to SN‐5 subitem scores at baseline and 1‐year elexacaftor/tezacaftor/ivacaftor. Comparison by Wilcoxon signed‐rank test, after having numerically transformed the scale (from 0 to 6): Sinus infection: p < 0.0001 (***); Nasal obstruction: p = 0.04 (*); Allergy symptoms: p = 0.09; Emotional distress: p = 0.44; Activity restrictions: p = 0.78.

FIGURE 4

Evolution of the Lund–Mackay total score and sinus specific subitems at baseline and 1‐year elexacaftor/tezacaftor/ivacaftor. Left panel: Total Lund–Mackay score. Data are presented as median, 25th and 75th percentiles, minimal and maximal value. The upper whisker extends from the hinge to the largest value. The lower whisker extends from the hinge to the smallest value. Comparison by Wilcoxon signed‐rank test, p < 0.0001. Right panel: Number of patients according to sinus specific Lund–Mackay subscore. Each sinus (left and right combined) was scored at M0 and M12. Comparison by Wilcoxon signed‐rank tests, all p‐values are < 0.0001 (***).