Real-world improvement in ultra-low-dose thoracic computed tomography scores, systemic inflammatory markers and patient-reported outcome measures after elexacaftor/tezacaftor/ivacaftor treatment

Abstract

Background Clinical trials with elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis were associated with significant improvements in % predicted forced expiratory volume in 1 s (FEV1 % pred), sweat chloride, weight and quality of life in the respiratory domain from the cystic fibrosis questionnaire revised (CFQ-R). Limited data exist on its effect on structural lung disease and inflammatory cytokines. Methods In a real-world setting with 61 people with cystic fibrosis, we prospectively recorded FEV1, sweat chloride, body mass index (BMI) and CFQ-R at baseline, 3 and 6 months after commencement of ETI. In addition, changes in ultra-low-dose (ULD) computed tomography (CT) Bhalla score, peripheral-blood and sputum inflammatory cytokines and patient-reported outcome measures (PROMs), including sino-nasal outcomes test-22 (SNOT-22) and fatigue scale (FACIT-Fatigue). Results Significant improvements in FEV1 % pred (p=0.0001), sweat chloride (p<0.0001) and BMI (p=0.0147) after ETI treatment were noted. ULD-CT scores demonstrated reductions in peri-bronchial thickening, mucus plugging and total Bhalla score (p<0.001), and improvements in emphysema extent (p<0.0027). Improvements in systemic inflammatory status were seen with a reduction in interleukin (IL)-1β (p=0.0049), IL-6 and IL-8 (p<0.0001), and increasing IL-10 (p=0.004). Sputum cytokine analysis was not performed as only four of 61 patients spontaneously expectorated sputum after ETI. PROMs improved significantly for the SNOT-22 (p<0.0001), FACIT-Fatigue score (p=0.0001) and CFQ-R domains, including respiratory (p<0.0001), physical (p=0.007), vitality (p=0.0004), treatment burden (p=0.0028), health (p=0.0007), social (p=0.0073), weight (p=0.0068) and role/school domain (p=0.0018). Conclusion ETI responders, demonstrate significant improvements in CT imaging, circulating cytokines and PROMs, which may be of further use evaluating cystic fibrosis transmembrane conductance regulator modulation treatment response.