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.