What question did this study set out to answer?

This study aims to evaluate the long-term biological effects of elexacaftor/tezacaftor/ivacaftor therapy on airway inflammation and infection in people with cystic fibrosis.

May 20, 2026

D91-10 Assessment of the Long-term Effects of Elexacaftor/Tezacaftor/Ivacaftor to Airway Inflammation and Infection of PWCF on Long-term ETI

Key Points

This study aims to evaluate the long-term biological effects of elexacaftor/tezacaftor/ivacaftor therapy on airway inflammation and infection in people with cystic fibrosis.
Eligible patients (N=50) receiving ETI therapy for 4-5 years were recruited from the adult CF Unit at Beaumont Hospital.
Bronchoscopies and BAL samples were taken from two sites for microbiome analysis and cytokine assessment.
Cytokine and protease levels were evaluated using ELISA and FRET for comprehensive analysis.
Lung function improved at 6 weeks on ETI therapy and remained stable for 4 years with fewer antibiotic courses and hospital admissions.
MSSA and NTHi were predominant pathogens found, with a notable increase in MRSA in the microbiome.
Cytokine levels varied between sampling sites, revealing localized inflammation not uniformly present across the lung.

Abstract

Abstract Rationale Cystic fibrosis (CF) is a progressive inherited disease, with 1 in 19 in Ireland being a carrier of the defective CFTR gene. Recent advancements in CFTR modulator therapy through elexacaftor, tezacaftor, ivacaftor (ETI) admission has shown remarkable clinical benefit in people with CF (PWCF). One corollary of ETI therapy is a reduction, and in some cases complete resolution of sputum production, limiting our ability to monitor disease. To address this we have instituted bronchoscopy evaluation in this cohort of PWCF in two locations, allowing for location specific airway sampling. This study aimed to further delineate the biological effects of long-term ETI therapy (4-5years) on inflammation and infection within the airway, and any regional variation therein. Methods Eligible patients (PWCF receiving ETI therapy for 4-5 years) were recruited in the adult CF Unit at Beaumont Hospital, Dublin, Ireland (N = 50). Bronchoscopies were conducted and BAL samples were taken from two discrete locations bilaterally. Samples were cultured on bacteria-specific agar to determine the presence of pre-determined targets often associated with CF exacerbated states, alongside whole genome sequencing for a complete picture of the microbiome. Cytokine and protease levels were assessed via ELISA and FRET respectively. Results Lung function significantly improved 6 weeks on ETI therapy. This improvement persisted for 4 years in our PWCF on ETI cohort, while antibiotic courses and hospital admissions remained lower than pre-ETI. However despite stabilised FEV1 levels, we have detected a shift in the microbiome of our PWCF cohort. In this cohort, MSSA and NTHi are predominant pathogens rather than PsA, alongside an increase in levels of MRSA. The levels of various cytokines, including IL-6, TNFR1 and IL-1β were detected at higher levels in one site relative to the other. Alongside these cytokines, our PWCF on ETI exhibited a neutrophil predominant side in correlation with neutrophil elastase activity. Interestingly, on expert review of the corresponding high resolution thoracic computed tomography (CT) images, it was found that the radiological distribution of disease sites of disease did not clearly correlate with cellular sites of inflammation within the lungs. Conclusion The use of BAL is a reproducible alternative to sputum for airway sampling in CF and affords much more detailed analysis of the alveolar space. CF is not a linear disease and does not present with universal inflammation across the whole lung, but instead presents with ‘pockets’ of worse inflammation, correlating with inflammatory cytokines, the microbiome, and protease activity. This abstract is funded by: Cystic Fibrosis Foundation

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