Real-World Improvements of Lung Clearance Index and Ventilation Distribution Efficiency in Children With Cystic Fibrosis After Elexacaftor/Tezacaftor/Ivacaftor Initiation

Abstract

Introduction: Elexacaftor/tezacaftor/ivacaftor (ETI) is a breakthrough therapy for cystic fibrosis (CF). We aimed to assess ETI's real-world impact on peripheral airway disease assessed as ventilation distribution inhomogeneity using nitrogen multiple breath washout (N₂MBW) in children aged 6-17 years. Additionally, we compared the two outcomes, lung clearance index (LCI), and ventilation distribution efficiency (VDE), as VDE is considered to adjust for a theoretical overestimation of lung disease when using LCI.

Methods: This nationwide study included data from N₂MBW performed during routine clinical care. Linear mixed effect regression was used to assess changes in LCI and VDE after 12 months of ETI treatment. Subgroup analyses included baseline age (6-11 vs. 12-1 years) and disease severity (normal-moderate vs. severe-very severe).

Results: We included 131 children (78% homozygous for F508del mutation, mean [SD] age 11.5 [3.4]), and 339 N₂MBW tests. The median (range) number of tests per child was 3 (1-10). The estimated mean (95% CI) 12-months post-ETI improvement in LCI and VDE were 1.7 units (-2.1; -1.2, p < 0.001) and 2.1%-point (1.6; 2.6, p < 0.001), respectively. Similar LCI and VDE improvements were observed across age groups. Using VDE, fewer children were categorized with very severe lung disease, and the ETI-effect did not differ between the severity groups, unlike LCI.

Conclusion: Our research demonstrates that ETI treatment significantly improves lung function, as measured by N₂MBW, in Danish children and adolescents with CF. VDE improvements were consistent across age and disease severity groups. In contrast, LCI revealed larger effect estimates for those with severe to very-severe lung impairment.

Keywords: LCI; VDE; cystic fibrosis; elexacaftor/tezacaftor/ivacaftor; real world study.

Figure 1

Consort diagram illustrating participant flow in upper panel and study period timeline with number of MBWs and patients tested before and after elexacaftor, tezacaftor, ivacaftor (ETI) treatment initiation in lower panel. ETI, elexacaftor/tezacaftor/ivacaftor; MBW, multiple breath washout. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Forest plot displaying estimated mean changes in VDE, LCI, and VDE z‐scores vs LCI z‐scores. Diamonds are mean model estimates 12 months post ETI therapy. Error bars visualize 95% CI. Estimates are based on mixed effects linear regression models adjusted for sex, prior CFTRm treatment, F508del genotype and Spiroware software version. (A) Absolute changes in VDE%, (B) Absolute changes in LCI, (C) Changes in VDE z‐scores versus LCI z‐scores. ETI, elexacaftor, tezacaftor, ivacaftor; LCI, Lung clearance index_2.5; VDE, ventilation distribution efficiency. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Lung clearance index_2.5 (LCI) and ventilatory distribution efficiency (VDE) before and after elexacaftor/tezacaftor/ivacaftor (ETI) initiation. Lines are based on mixed effects linear regression models adjusted for sex, prior CFTRm treatment, F508del genotype and Spiroware software version. Of the 131 children included, 88 (67%) had paired N₂MBW measurements before and after ETI initiation, while 31 had only pre‐ETI and 12 had only post‐ETI measurements. Red ribbon + solid line: development of LCI and VDE over time before ETI treatment. Green ribbon + solid line: Development of LCI and VDE over time after ETI treatment. Yellow ribbon + dashed line: Projected development of LCI without ETI treatment. Red dashed vertical line: 12 months marker indicating the time point of estimated treatment effect. ETI, elexacaftor, tezacaftor, ivacaftor; LCI, Lung clearance index_2.5; VDE, ventilation distribution efficiency. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Changes in lung disease severity groups based on LCI and VDE z‐scores. River‐plot of changes in lung disease severity groups based on LCI and VDE z‐scores among 88 children with cystic fibrosis comparing LCI and VDE at baseline and 12 months following ETI treatment. In children with multiple measurements before and after, the severity group was based on their mean LCI and VDE z‐scores before, and after treatment initiation. The curved bands between the “before ETI” and “after ETI” columns reflect the numbers of patient in each category that changes or noncurved that stays in the same category. ETI, elexacaftor, tezacaftor, ivacaftor; LCI, lung clearance index_2.5; VDE, ventilation distribution efficiency. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 5

Agreement between LCI and VDE z‐score–based severity group classifications before ETI initiation. The heatmap displays the percentage of patients within each LCI z‐score severity group (rows) classified into the corresponding VDE z‐score severity group (columns). Darker shades indicate higher agreement. Most patients were classified into the same or adjacent categories, with 93% overall agreement. No patients were misclassified by more than one category. [Color figure can be viewed at wileyonlinelibrary.com]