Effects of highly effective modulator therapy on the dynamics of the respiratory mucosal environment and inflammatory response in cystic fibrosis

Abstract

BackgroundWhile the widespread initiation of elexacaftor/tezacaftor/ivacaftor (ETI) has led to dramatic clinical improvements among persons with cystic fibrosis (pwCF), little is known about how ETI affects the respiratory mucosal inflammatory and physiochemical environment, or how these changes relate to lung function.MethodsWe performed a prospective, longitudinal study of adults with CF and chronic rhinosinusitis (CF‐CRS) followed at our CF center (n = 18). Endoscopic upper respiratory tract (paranasal sinus) aspirates from multiple visit dates, both pre‐ and post‐ETI initiation, were collected and tested for cytokines, metals, pH, and lactate levels. Generalized estimating equations were used to identify relationships between ETI and upper respiratory tract (URT) biomarker levels, and between URT biomarkers and lung function or clinical sinus parameters.ResultsETI was associated with decreased upper respiratory mucosal cytokines B‐cell activating factor (BAFF), IL‐12p40, IL‐32, IL‐8, IL‐22 and soluble tumor necrosis factor‐1 (sTNFR1), and an increase in a proliferation‐inducing ligand (APRIL) and IL‐19. ETI was also associated with decreased URT levels of copper, manganese, and zinc. In turn, lower URT levels of BAFF, IL‐8, lactate, and potassium were each associated with ~1.5% to 4.3% improved forced expiratory volume in 1 s (FEV1), while higher levels of IFNγ, iron, and selenium were associated with ~2% to 10% higher FEV1.ConclusionsOur observations suggest a dampening of inflammatory signals and restriction in microbial nutrients in the upper respiratory tract with ETI. These findings improve our understanding of how ETI impacts the mucosal environment in the respiratory tract, and may give insight into the improved infectious and inflammatory status and the resulting clinical improvements seen in pwCF.

Persistence and evolution of Pseudomonas aeruginosa following initiation of highly effective modulator therapy in cystic fibrosis

“…We found that P. aeruginosa undergoes a population bottleneck coincident with the initiation of ETI, followed by drastic changes to the mutational spectra of the P. aeruginosa population due to new selective pressures in the post-ETI airway environment. This bottleneck is likely explained by changes in the CF respiratory environment caused by corrected CFTR function, which we have recently reported ( 6 ); anecdotally, some individuals with advanced CF lung disease experienced severe cough and copious sputum production in the first few days post-ETI ( 7 ). The widespread use and success of HEMT in CF has sparked an interest in changes to CF disease management toward reducing the medication burden in people taking ETI ( 8 ).…”

CFTR dysfunction leads to defective bacterial eradication on cystic fibrosis airways

“…Recently FDA-approved triple therapy with elexacaftor/tezacaftor/ivacaftor (ETI) ( Keating et al, 2018 ; Heijerman et al, 2019 ; Middleton et al, 2019 ) has been used to treat people with cystic fibrosis carrying at least one ΔF508 allele ( Tummler, 2023 ), in which ivacaftor (VX-770) acts as a potentiator to enhance the channel activity of the ΔF508 or G551D mutants ( Van Goor et al, 2009 ); tezacaftor (VX-661) ( Rowe et al, 2017 ; Taylor-Cousar et al, 2017 ) and elexacaftor (VX-445) ( Keating et al, 2018 ; Laselva et al, 2021 ) work as correctors but elexacaftor also partially acts as a potentiator ( Laselva et al, 2021 ). The promising outcomes show that the combination treatment substantially recovers CF lung function by reducing pulmonary exacerbations and hospitalizations per patient per year ( Bower et al, 2023 ), improving percent predicted forced expiratory volume in 1 s (ppFEV1) up to 10% ( Bower et al, 2023 ; Atteih et al, 2024 ), diminishing the release of inflammatory mediators, such as the B cell activating factors, IL-6, IL-8 and IL-22, C-reactive protein and soluble TNF ( Casey et al, 2023 ; Schaupp et al, 2023 ; Atteih et al, 2024 ), advancing sputum viscoelastic properties ( Schaupp et al, 2023 ), lowering the sweat Cl − concentration and lung clearance index 2.5 ( Goralski et al, 2023 ), and decreasing the detection and diversity of bacteria like S. aureus and P. aeruginosa in CF microbiological samples ( Dittrich et al, 2024 ) and sputum ( Nichols et al, 2023 ; Schaupp et al, 2023 ). Notably, ETI treatment is safe for use in children aged 2–5 years ( Goralski et al, 2023 ) and pregnant women ( Cimino et al, 2024 ).…”