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

Abstract Background While 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. Methods We 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. Results ETI 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 (FEV 1 ), while higher levels of IFNγ, iron, and selenium were associated with ~2% to 10% higher FEV 1 . Conclusions Our 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.