Rationale: Modulation of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein improves clinical outcomes in patients with CF and specific CFTR genetic mutations. It remains unclear how improving CFTR function modifies existing airway infection and inflammation.Objectives: To compare sputum microbiome and markers of inflammation before and after 6 months of ivacaftor treatment. Methods:The study included 31 people with CF, ages 10 years and older, with at least one G551D CFTR allele and an forced expiratory volume in 1 second (FEV 1 ) of 40% predicted or greater who were enrolled in the GOAL (G551D Observational) study. Sputum samples were collected either by induction (n = 14) or by spontaneous expectoration (n = 17) before and 6 months after initiation of ivacaftor. Changes in bacterial community indices by sequencing of 16S rRNA amplicons, total and specific bacterial load, and a panel of proteases, antiproteases, and inflammatory cytokines were determined. Results:The cohort that spontaneously expectorated sputum had a lower FEV 1 , a higher proportion with Pseudomonas aeruginosa infection, and higher concentrations of sputum inflammatory markers compared with the cohort that provided sputum by induction. Although the overall cohort experienced significant improvements in FEV 1 and reductions in sweat chloride, no significant changes in bacterial diversity, specific bacterial pathogens, or markers of inflammation were observed in these subjects. Neither total bacterial load nor presence of Pseudomonas changed significantly between paired samples with ivacaftor treatment. Younger patients experienced more shifts in their microbial communities than older patients.Conclusions: In this multicenter cohort, 6 months of ivacaftor treatment were not associated with significant changes in airway microbial communities or measures of inflammation. These data suggest that concomitant antimicrobial and antiinflammatory treatments will still be needed to manage airway disease in patients with CF treated with highly effective CFTR modulator therapy, especially in older patients with more advanced disease.

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A divergent trial design that evaluates subjects' interim improvement in FEV and symptoms to tailor randomization to IV treatment duration (10 vs. 14days for ERR, 14 vs. 21days for NERR) may alleviate physician and patient concerns about excess or inadequate treatment. Such a study has the potential to provide evidence necessary to standardize IV antibiotic duration in CF PEx care -a first step to conducting PEx research of other treatment features.

Rationale: Understanding how cystic fibrosis transmembrane conductance regulator (CFTR) modulators influence comorbid conditions like anemia is of great interest to the cystic fibrosis community. Objectives: To test the hypothesis that CFTR modulators are associated with higher hemoglobin (Hgb) levels. Methods: Annualized Hgb and other laboratory, demographic, and anthropometric data were abstracted from the U.S. CF Foundation Patient Registry for adult and pediatric registrants before and after therapy with ivacaftor (IVA) or lumacaftor/ivacaftor (LUM/IVA) between January 2010 and December 2016. Univariate and multivariate linear mixed models were used to examine the effect of IVA on Hgb in patients with G551D-CFTR, and the effect of LUM/ IVA on Hgb in F508del-CFTR homozygotes. Linear regression was used to characterize change in mean Hgb over time. Results: A total of 1,347 registrants (707 males and 640 females) with G551D-CFTR and 12,582 F508del-CFTR homozygotes (6,640 males and 5,942 females) who had never undergone lung transplant and had contemporaneous data regarding Hgb and CFTR modulator use were identified. IVA was associated with average Hgb increases of 0.54 gm/dl (95% confidence interval [CI], 0.39-0.69; P , 0.0001) and 0.18 gm/dl (95% CI, 0.01-0.35; P = 0.037) for males and females, respectively, with G551D-CFTR. LUM/IVA was associated with average Hgb increases of 0.58 gm/dl (95% CI, 0.48-0.68; P , 0.0001) and 0.26 gm/dl (95% CI, 0.20-0.33; P , 0.0001) for male and female F508del-CFTR homozygotes, respectively. In multivariate models, IVA positively affected Hgb in males but not females, and LUM/IVA positively affected Hgb in both sexes. Conclusions: IVA and LUM/IVA use are both associated with higher Hgb levels in patients with CF.