EPS6.04 Elexacaftor/tezacaftor/ivacaftor (ETI) reduces sputum pathogen density and lung inflammation, but infection and inflammation persist

Abstract

The effects of modulators on lung infection and inflammation are unclear. We present 2 studies examining ETI’s effects on infection and inflammation. The first (PROMISE-Micro), tested the hypothesis that ETI improves lung infections. Sputum from 236 participants was studied using culture, PCR and sequencing. Average sputum density of Staphylococcus aureus, Pseudomonas aeruginosa (Pa), and other CF pathogens decreased ~100-fold after 1 month, with little further change through 2 years of follow-up. However, most participants remained culture-positive for pathogens present before starting ETI. Sequencing found increased sputum bacterial diversity and shifts in bacterial composition. However, these changes were caused by treatment-induced decreases in a small group of pathogens. The second study tested the hypothesis that lung regions with persistent infection would remain inflamed after ETI. We used bronchoscopy to lavage the same 5 lung segments before and 1.5 years after ETI in 9 participants chronically infected with Pa. ETI reduced average lavage Pa density by ~200-fold and neutrophil elastase (NE) by ~9-fold. NE became undetectable in almost all (16/18) segments becoming Pa negative. However, 27 lung segments (in 6 participants) remained Pa infected and inflamed. The correlation between Pa density and NE level in lung segments increased after ETI (R2 from 0.28 to 0.76) suggesting that Pa density better accounts for observed NE levels post-ETI. The NE level associated with each log10 Pa was unchanged pre- and post-ETI, indicating that a given level of Pa produces similar lung inflammation regardless of ETI use. IL-1b, IL-8, and IL-6 also decreased more in segments becoming culture-negative verses those remaining Pa-infected.