Impact of 2 years of treatment with elexacaftor/tezacaftor/ivacaftor on longitudinal changes in structural lung disease in people with cystic fibrosis: results from the RECOVER trial

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RATIONALE: Progressive structural lung disease (SLD) is a key hallmark of cystic fibrosis (CF). Elexacaftor/tezacaftor/ivacaftor (ETI) is associated with short-term improvements in SLD measured on chest computed tomography (CT). Longer-term changes in SLD outcomes with ETI are unknown. OBJECTIVES: Using multicenter standardized image collection and automated analysis, we sought to establish whether improvements in SLD with ETI continued in the second year of treatment. METHODS: Spirometry-controlled CT scans were performed at 6 sites in people with CF aged ≥12 years homozygous for the F508del mutation or heterozygous for the F508del and a minimum function mutation at baseline and 12 months and 24 months after commencing ETI. CT scans were analyzed using the automated LungQ platform (Thirona) to measure mucus plugging, trapped air, and bronchus-artery (BA) pair measurements: bronchial outer diameter (Bout), bronchial inner diameter (Bin), bronchial wall thickness (Bwt), arterial diameter (A), and BA ratios: Bout/A, Bin/A, Bwt/A, and bronchial wall area/bronchial outer area (Bwa/Boa). Scans were also visually scored using the PRAGMA-CF scoring system, divided into % disease (%DIS), % bronchiectasis (%BX), % mucus plugging (%MP), % bronchial wall thickening (%BWT), and % trapped air (%TA). RESULTS: CT scans were performed on 79 participants at baseline, 64 at 12 months, and 52 at 24 months. Automated analysis showed a significant reduction BwtA, and Bwa/Boa at 12 months, which were sustained to 24 months. No change was seen in Bin/A or Bout/A at 12 or 24 months. Improvements in mucus plug numbers, plug volume, and %TA at 12 months were sustained at 24 months. ETI was associated with a reduction in the ratio of pulmonary blood volume in the arterial system compared to the venous system in vessels of <1 mm, 1-2 mm, and >2 mm diameter. Manual PRAGMA-CF scores demonstrated improvements in %DIS, %BX, %MP, %BWT, and %TA at 12 months, and these changes were sustained, unchanged to 24 months. CONCLUSIONS: ETI is associated with substantial improvements in bronchial wall thickening, mucus plugging, and trapped air at 12 months. Changes were maintained to 24 months and did not continue to improve. Abnormal bronchial widening remained stable and did not improve with ETI therapy. Changes in the distribution of pulmonary arterial/venous blood volumes with ETI suggest a beneficial impact on pulmonary vascular pressures.

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