Lung T1-MRI and Multi-Breath Washout Detect Longitudinal Changes in Children 6-11 Years Old After Beginning Elexacaftor/Tezacaftor/Ivacaftor (ETI) Therapy.

BACKGROUND

Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy was approved in 2021 for clinical use in children with CF (cwCF) age 6-11 years, depending on their genetic variants. Our prior multi-center study showed that lung T1-MRI and multi-breath washout (MBW) provided complementary pathobiological information on CF lung disease in cwCF 6-11 years of age. In this study, we hypothesized that lung T1-MRI and MBW will sensitively detect lung improvements in cwCF after starting ETI therapy. To test this hypothesis, we obtained longitudinal lung T1-MRI, MBW, and spirometry assessments in a cohort of cwCF 6-11 years of age before and after starting ETI therapy.

METHODS

CwCF (n = 48, mean age = 8.6 years) were recruited from 3 cystic fibrosis (CF) centers (Riley Hospital for Children (Indianapolis, IN), University of Michigan, Michigan Medicine (Ann Arbor, MI), and Rainbow Babies and Children's Hospital (Cleveland, OH) for longitudinal lung T1-MRI, MBW, and spirometry assessments before initiating ETI (baseline) as well as at 3-months and 6-months after initiating ETI. MBW and spirometry were performed according to published guidelines to obtain measurements of the lung clearance index (LCI) and percent predicted forced expiratory volume at 1 s (ppFEV1), and percent predicted forced expiratory flow at 25%-75% (FEF25 %-75%), respectively. Lung T1-MRI was used to obtain assessments of % normal lung perfusion (%NLP). An ANOVA analysis and descriptive statistics were used to compare the longitudinal changes in the lung T1-MRI, MBW, and spirometry findings.

RESULTS

Across all subjects, significant improvements in both spirometry (ppFEV1, FEF25 %-75%) and MBW (LCI 2.5) were observed at 3-months, and 6-months post treatment (p < 0.001). As a group, the lung T1-MRI findings showed no significant changes despite a trend for improved lung perfusion. However, lung T1-MRI did show a significant improvement in both 3-months and 6-months after starting ETI therapy (p < 0.03) when evaluating only those subjects with mild-moderate lung disease (ppFEV1 ≤ 90 % ) $\le 90 \% )$ at baseline.

CONCLUSIONS

MBW, spirometry, and lung T1-MRI are all capable of detecting lung airway and perfusion changes in cwCF 6-11 years of age following the start of ETI therapy. MBW and spirometry assessments were able to detect a sustained improvement in pulmonary function testing regardless of baseline lung status, while lung T1-MRI was able to detect significant improvements in lung perfusion in patients with more advanced lung disease. These findings, in combination with our prior cross-sectional findings, suggest that MBW and lung T1-MRI may provide complementary alternatives to chest CT and can be used to assess disease progression and/or response to therapy.