Discussion
The Use of ETI in eligible PwCF was associated with a marked decrease in markers of inflammation in BAL and fewer positive cultures from BAL fluid. While consistent with the known pathophysiology of CF, this result differs from prior studies of ivacaftor alone that have not shown a clear impact on airway inflammation or infection despite substantial clinical benefit.4 It is possible that ETI results in greater restoration of CFTR activity than ivacaftor alone in eligible genotypes, and clinical studies have suggested a clinical benefit of ETI in patients previously treated with ivacaftor.6However, further investigation will be necessary to confirm these findings and better understand the differences between ETI therapy and ivacaftor alone.
The failure of ivacaftor alone to substantially reduce airway inflammation in treated patients has suggested that individuals on HEMT may still benefit from anti-inflammatory therapies. Our findings suggest that anti-inflammatory therapies may be less effective for many treated with ETI, although substantial levels of airway inflammation remained in some PwCF on ETI. It is not clear if this reflects therapeutic failure of ETI to effectively improve CFTR activity or the presence of established structural lung disease that led to continued inflammation and infection despite normal levels of CFTR. Regardless, the findings indicate that individualized strategies will be needed to optimize efficacy of ETI and/or identify those who continue to need anti-inflammatory or other treatments despite HEMT.
Strengths of this study include use of bronchoscopy with BAL as the gold standard measure of airway inflammation. Limitations include the small size and reliance on clinically indicated procedures and findings for analysis. Therefore, measures such as neutrophil elastase or cytokines that are not routinely performed clinically were not available.
In conclusion, 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.