(564) Regional lung sampling after elexacaftor/tezacaftor/ivacaftor reveals Pseudomonas aeruginosa persistence in high and low damage segments

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function, reduces sputum pathogen density, and dampens pro-inflammatory mechanisms in CF cells. Despite these remarkable benefits, most people infected with Pseudomonas aeruginosa (Pa) remain infected after treatment. The mechanisms explaining persistent infection and the relationship between lung infection and inflammation after ETI are unknown. We tested two hypotheses. (1) In patients with persistent post-modulator Pa infections, lung regions with mild damage would frequently clear, whereas regions with severe damage would remain infected. (2) Despite ETI’s effects in abrogating pro-inflammatory mechanisms, lung regions with persistent Pa infection would remain inflamed, and the extent of regional inflammation would correlate with Pa density.

Methods: We ranked lung segments of chronically infected subjects by the degree of structural damage on pre-ETI CT scans. We then used bronchoscopy to sample the airways of the two lung segments with the most severe damage and the three segments with the least severe damage. To reduce between-region contamination, a new disposable bronchoscope was used for each segment and washings were collected after wedging. The same lung regions in each subject were sampled again after 18 months of ETI, and Pa density and the inflammatory marker neutrophil elastase were measured.

Results: In all nine subjects almost all sampled lung segments were culture positive before starting ETI (seven subjects had Pa in 5/5 sampled regions, two had Pa in 4/5 regions). After ETI, in four subjects, no regions cleared Pa, and in two subjects, only one region cleared Pa. The remaining three subjects cleared Pa from all five regions. Pa clearance after ETI did not differ in lung regions with mild vs. severe structural damage. Moreover, Pa culture density decreased similarly in regions with high and low structural damage.

We observed a strong association between neutrophil elastase (NE) levels and Pa culture density before and after ETI (p< 0.0001). Indeed, the coefficient of determination (R² value) between these variables was higher post-ETI than pre-ETI (R²=0.76 vs 0.31), and the ETI-associated change in Pa density and NE levels strongly correlated (p=0.0001; R²=0.43). Moreover, NE was undetectable in 16 of 18 Pa-negative segments after ETI, whereas NE was undetectable in only 5 of 27 Pa-positive segments.

Conclusions: We examined the relationship between regional lung damage and regional infection clearance post ETI. Our findings contradict the hypothesis that non-resolving lung infection after modulators is explained by pathogen persistence in structurally damaged regions. Instead, we found that Pa persisted in lung regions with mild and severe injury in subjects that remained Pa-infected. This suggests that Pa clearance may depend on patient- or strain-specific factors rather than the extent of region-specific damage.



We also examined the relationship between regional lung pathogen density and regional inflammation. Our findings support the hypothesis that regional NE in patients on ETI correlates with regional Pa density. Indeed, correlations between these parameters increased after ETI, and NE was generally only detectable in Pa-positive segments. These findings suggest that modulators’ primary inflammation-dampening effects may not alleviate inflammation in persistently infected lung regions.

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