(161) Elexacaftor/Tezacaftor/Ivacaftor reduces trapped gas in children with cystic fibrosis

Background: Mucus plugging, one of the features of early cystic fibrosis (CF) pathophysiology, can lead to poorly ventilated areas in the lung that are incompletely emptied during tidal breathing. The volume of gas retained within these lung units is referred to as trapped gas and can be assessed by different modalities such as Multiple Breath Washout (MBW) or functional imaging. During MBW, the volume of trapped gas (VTG) can be quantified by adding a series of inspiratory capacity breaths at the end of a standard Nitrogen (N₂) MBW test to recruit lung regions that release residual N₂ [1]. VTG has been shown to be elevated in CF, but it is currently unknown whether VTG captures changes following Elexacaftor/Tezacaftor/Ivacaftor.

Methods: This is a single center add-on study of participants enrolled in one of two ongoing studies: the multi-center HyPOINT (HyperPOlarized Imaging of New Therapies, NCT04259970) study and a SickKids based observational study of participants initiated on CFTR-Modulator treatment. In this study protocol the following tests were performed at baseline and 1-month after start of Elexacaftor/Tezacaftor/Ivacaftor. N₂ MBW was performed using the Exhalyzer®D MBW device and Spiroware 3.3.1 software (EcoMedics, Duernten, Switzerland). Lung clearance index (LCI) and VTG were reported, with VTG expressed as percent of forced vital capacity measured by spirometry (VTG/FVC%). Hyperpolarized ¹²⁹Xenon magnetic resonance imaging (Xe-MRI) as well as free-breathing MRI were also performed at each visit for participants enrolled in the HyPOINT study. Using the Phase Resolved FUnctional Lung (PREFUL) method, fractional ventilation (FV) maps were determined from free-breathing images [2]. Ventilation Defect Percent (VDP) was calculated both from Xe-MRI ventilation images (VDP_Xe) based on a threshold of 60% of the mean ventilation signal, as well as FV maps (VDP_FV), using k-means clustering [2]. Statistical analysis included Wilcoxon rank sign test for pre and post comparisons and Spearman test for correlations.

Results: To date, 10 participants, median (range) age 16.2 (13.5-18.6) years, have completed MBW at both visits; recruitment is ongoing. At baseline, median (range) LCI was 9.66 (6.22-16.08) and FEV₁ 73 (43-95) % predicted. Across the two visits, median (IQR) LCI decreased from 9.66 (7.43-11.39) to 7.73 (6.51-8.91) (p=0.04) while FEV₁ increased from 72 (66-80) to 88 (78-99) % predicted. VTG/FVC% significantly decreased from 3.47 (2.40-6.23) to 1.36 (0.89-3.61)% (p< 0.01). Relative difference in VTG/FVC% correlated with relative change in VDP_Xe (r= 0.71, p=0.05, Figure 1A) as well as with VDP_FV (r= 0.86, p< 0.01, Figure 1B).

Conclusions: Trapped gas, as measured by VTG/FVC% during MBW, decreases after the start of highly effective CFTR modulator therapy and correlates well with changes measured by functional MRI.

Acknowledgements: This work was supported the Cystic Fibrosis Foundation.

References: [1] Gustafsson PM, Johansson HJ, Dahlbäck GO. Pneumotachographic nitrogen washout method for measurement of the volume of trapped gas in the lungs. Pediatric pulmonology. 1994 Apr;17(4):258-68.

[2] Couch MJ, Munidasa S, Rayment JH, Voskrebenzev A, Seethamraju RT, Vogel-Claussen J, Ratjen F, Santyr G, Comparison of Functional Free-Breathing Pulmonary 1H and Hyperpolarized 129Xe Magnetic Resonance Imaging in Pediatric Cystic Fibrosis. Academic Radiology. 2021 Aug; 28(8):e209-e218.