Impact of two years of treatment with Elexacaftor/Tezacaftor/Ivacaftor on longitudinal changes in structural lung disease in people with Cystic Fibrosis – Results from the RECOVER trial

Abstract Rationale Progressive structural lung disease (SLD) is a key hallmark of cystic fibrosis. The CFTR modulator combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) is associated with short term improvements in SLD measured on chest CT by visual scoring systems. Longer term changes in structural lung disease outcomes with ETI are unknown. Objectives Using multi-centre standardized image collection and automated analysis, we sought to establish whether improvements in structural lung disease with ETI continued in the second year of treatment. Methods Spirometry controlled CT scans using standardised protocols at 6 sites were performed in people with CF aged 12 and older homozygous for the F508del mutation (FF) or heterozygous for the F508del and a minimum function mutation (FMF) at baseline, 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 Perth Rotterdam Annotated Grid Morphometric Analysis (PRAGMA-CF) scoring system, divided into % disease (%DIS), % bronchiectasis (%BX), % Mucus plugging (%MP), % bronchial wall thickening (%BWT) and % trapped air (%TA). Measurements and Main 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 in the number of visible BA-pairs, BwtAand 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 < 1mm, 1-2mm and >2mm 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 Automated analysis of spirometry-controlled chest CT images in people with CF aged 12 years and older showed that the substantial improvements in bronchial wall thickening, mucus plugging and trapped air seen at 12 months were maintained at 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 suggests a beneficial impact on pulmonary vascular pressures.