To the Editor, Airway mucus dehydration from loss of cystic fibrosis transmembrane conductance regulator (CFTR) activity leads to excessive airway muco-inflammation that drives the onset and progression of lung disease in cystic fibrosis (CF.) 1,2 Previous studies with the highly effective modulator therapy (HEMT) ivacaftor have demonstrated improvement in CFTR function and substantial clinical benefits. However, clinical studies of ivacaftor therapy in people with CF (PwCF) with eligible genotypes have not consistently demonstrated a significant reduction in markers of airway inflammation. 3,4 This somewhat unanticipated result suggests that airway inflammation may persist in PwCF on HEMT and could benefit from anti-inflammatory therapies.Recently, elexacaftor-tezacaftor-ivacaftor (ETI, Trikafta) was approved as a HEMT available to a larger fraction of PwCF. While in vitro evidence suggests that ETI treatment may alter inflammatory pathways in CF, 5 there is little information regarding the impact of ETI on airway inflammation in treated individuals. To address this issue, we identified PwCF who underwent bronchoscopy with bronchoalveolar lavage (BAL) after starting ETI therapy. To avoid confounding by indication, the study population was limited to those who had surveillance procedures before and after starting ETI therapy. BAL markers of inflammation and infection obtained during these procedures were then compared.

ETI treatment reduces inflammatory markers and positive bacterial cultures on BAL in PwCF. These findings suggest that ETI has a greater impact on chronic infection and inflammation than ivacaftor alone. However, airway inflammation persists in a fraction of treated individuals, indicating an ongoing need to optimize other treatments in a subset of patients.