People with cystic fibrosis with high sputum neutrophil elastase on elexacaftor-tezacaftor-ivacaftor exhibit worse pulmonary function and pro-inflammatory airway milieu

Cystic fibrosis (CF) is a genetic condition affecting over 100,000 individuals worldwide. Lung disease is the main cause of mortality in CF, with chronic neutrophilic inflammation as a hallmark. Elexacaftor/tezacaftor/ivacaftor (ETI) is a combination of highly effective CF transmembrane conductance regulator (CFTR) modulators, conferring significant pulmonary gains to treated patients. However, the extent to which ETI controls inflammation is uncertain. To investigate this, we quantified effector proteins, cytokines, and metabolites in sputum fluid supernatant from ETI-treated (n = 32) and treatment-naïve (n = 9) people with CF (pwCF). ETI-treated pwCF showed detectible ivacaftor and tezacaftor in sputum, and overall lower sputum neutrophil elastase (NE) activity than ETI-naïve pwCF, although they displayed a clear bimodal distribution NEHi: median of 1415.3 ng/mL (IQ: 1113.6-1500.9), NELo: 83.2 ng/mL (IQ: 0-165.9). NEHi pwCF on ETI had higher levels of pro-inflammatory mediators, including IL-1β, IL-6 and TNF-α, MPO activity, and 107 metabolites associated with purine metabolism, proteolysis, and oxidative stress. These findings suggest pwCF on ETI who have high airway NE activity also have high inflammatory burden and a history of lower pulmonary function. Adjunctive neutrophil-targeted interventions may be beneficial for these individuals to receive maximal benefits from ETI therapy.