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Cystic fibrosis (CF) remains the most common life-shortening hereditary disease in white populations, with high morbidity and mortality related to chronic airway mucus obstruction, inflammation, infection, and progressive lung damage. In 1989, the discovery that CF is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene that encodes a cAMP-dependent anion channel vital for proper Cl - and HCO 3 - transport across epithelial surfaces provided a solid foundation for unraveling underlying disease mechanisms and the development of therapeutics targeting the basic defect in people with CF. In this review, we focus on recent advances in our understanding of the molecular defects caused by different classes of CFTR mutations, implications for pharmacological rescue of mutant CFTR, and insights into how CFTR dysfunction impairs key host defense mechanisms, such as mucociliary clearance and bacterial killing in CF airways. Furthermore, we review the path that led to the recent breakthrough in the development of highly effective CFTR-directed therapeutics, now applicable for up to 90% of people with CF who carry responsive CFTR mutations, including those with just a single copy of the most common F508del mutation. Finally, we discuss the remaining challenges and strategies to develop highly effective targeted therapies for all patients and the unprecedented potential of these novel therapies to transform CF from a fatal to a treatable chronic condition.

Rationale: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence., Objectives: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence., Methods: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS., Measurements and Main Results: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints., Conclusions: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Rationale: Individuals with cystic fibrosis (CF) experience frequent acute pulmonary exacerbations, which lead to decreased lung function and reduced quality of life., Objectives: The goal of this study was to determine if an intervention directed toward early detection of pulmonary exacerbations using home spirometry and symptom monitoring would result in slower decline in lung function than in control subjects., Methods: We conducted a multicenter, randomized trial at 14 CF centers with subjects at least 14 years old. The early intervention arm subjects measured home spirometry and symptoms electronically twice per week. Sites were notified if a participant met criteria for an exacerbation and contacted participants to determine if treatment for acute exacerbation was required. Participants in the usual care arm were seen every 3 months and were asked to contact the site if they were concerned about worsening pulmonary symptoms., Measurements and Main Results: The primary outcome was the 52-week change in FEV 1 . Secondary outcomes included time to first exacerbation and subsequent exacerbation, quality of life, and change in weight. A total of 267 patients were randomized, and the study arms were well matched at baseline. There was no significant difference between study arms in 52-week mean change in FEV 1 slope (mean slope difference, 0.00 L, 95% confidence interval, -0.07 to 0.07; P = 0.99). The early intervention arm subjects detected exacerbations more frequently than usual care arm subjects (time to first exacerbation hazard ratio, 1.45; 95% confidence interval, 1.09 to 1.93; P = 0.01). Adverse events were not significantly different between treatment arms., Conclusions: An intervention of home monitoring among patients with CF was able to detect more exacerbations than usual care, but this did not result in slower decline in lung function. Clinical trial registered with www.clinicaltrials.gov (NCT01104402).

Rationale: Pseudomonas aeruginosa undergoes phenotypic changes during cystic fibrosis (CF) lung infection. Although mucoidy is traditionally associated with transition to chronic infection, we hypothesized that additional in vitro phenotypes correlate with this transition and contribute to disease., Objectives: To characterize the relationships between in vitro P. aeruginosa phenotypes, infection stage, and clinical outcomes., Methods: A total of 649 children with CF and newly identified P. aeruginosa were followed for a median 5.4 years during which a total of 2,594 P. aeruginosa isolates were collected. Twenty-six in vitro bacterial phenotypes were assessed among the isolates, including measures of motility, exoproduct production, colony morphology, growth, and metabolism., Measurements and Main Results: P. aeruginosa phenotypes present at the time of culture were associated with both stage of infection (new onset, intermittent, or chronic) and the primary clinical outcome, occurrence of a pulmonary exacerbation (PE) in the subsequent 2 years. Two in vitro P. aeruginosa phenotypes best distinguished infection stages: pyoverdine production (31% of new-onset cultures, 48% of intermittent, 69% of chronic) and reduced protease production (31%, 39%, and 65%, respectively). The best P. aeruginosa phenotypic predictors of subsequent occurrence of a PE were mucoidy (odds ratio, 1.75; 95% confidence interval, 1.19-2.57) and reduced twitching motility (odds ratio, 1.43; 95% confidence interval, 1.11-1.84)., Conclusions: In this large epidemiologic study of CF P. aeruginosa adaptation, P. aeruginosa isolates exhibited two in vitro phenotypes that best distinguished early and later infection stages. Among the many phenotypes tested, mucoidy and reduced twitching best predicted subsequent PE. These phenotypes indicate potentially useful prognostic markers of transition to chronic infection and advancing lung disease.

Rationale: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation., Objectives: To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers., Methods: We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor., Conclusions: Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.

Rationale: Although previous studies suggest that access to care for patients with cystic fibrosis (CF) does not vary appreciably by socioeconomic status (SES), disparities with respect to access to lung transplantation for patients with CF are largely unknown., Objectives: To determine whether access to lung transplantation for patients with CF differs according to SES., Methods: Observational study involving 2,167 adult patients with CF from the CF Foundation Patient registry who underwent their first lung transplant evaluation between 2001 and 2009. The primary outcome was acceptance for lung transplant after initial evaluation. The main SES indicator was Medicaid status. Alternate SES indicators included race, educational attainment, ZIP code-level median household income, and driving time from residence to closest lung transplant center., Measurements and Main Results: The odds that Medicaid recipients were not accepted for lung transplant were 1.56-fold higher (95% confidence interval [CI], 1.27-1.92) than patients without Medicaid, after multivariate adjustment for demographic characteristics, disease severity, and potential contraindications to lung transplant, and before or after use of the lung allocation score. This association was independent of other SES indicators, including race, educational attainment, ZIP code-level median household income, and driving time to closest transplant center (odds ratio [OR] = 1.37; 95% CI, 1.10-1.72). Patients not completing high school (OR = 2.37; 95% CI, 1.49-3.79) and those residing in the lowest (vs. highest) ZIP code median household income category (OR = 1.39; 95% CI, 1.01-1.93) also experienced a higher odds of not being accepted for lung transplant in multivariate analysis., Conclusions: In this nationally representative study of adult patients with CF, multiple indicators of low SES were associated with higher odds of not being accepted for lung transplant.

Rationale: Adults with cystic fibrosis (CF) possess multiple potential risk factors for chronic kidney disease, including CF-related diabetes (CFRD) and lifetime nephrotoxic drug exposure., Objectives: To determine whether cumulative intravenous (IV) aminoglycoside exposure and CFRD increase the risk of chronic kidney disease in adults with CF., Methods: This was a cohort study using adults (≥ 18 yr) in the CF Foundation registry from 2001-2008. Chronic kidney disease (stage 3 or greater) was defined by an estimated glomerular filtration rate of less than 60 ml/min/1.73 m(2). Time-dependent multivariable Cox proportional hazards models were used to determine whether cumulative number of acute pulmonary exacerbations (surrogate for IV aminoglycoside exposure) and CFRD requiring insulin increase the risk of chronic kidney disease, adjusting for confounders., Measurements and Main Results: The study cohort included 11,912 adults with a median follow-up of 4 years. During the study period, 204 subjects had chronic kidney disease, with an annual disease prevalence of 2.3%. Disease prevalence doubled with every 10-year increase in age. CFRD requiring insulin therapy substantially increased the risk of chronic kidney disease (1-4 yr of CFRD requiring insulin vs. no CFRD, hazard ratio [HR] = 2.40, 95% confidence interval [CI] 1.74-3.32; ≥ 5 yr, HR = 4.56, 95% CI 2.84-7.31). Pulmonary exacerbations did not significantly increase the risk of chronic kidney disease (one to five exacerbations vs. none, HR = 0.79, 95% CI 0.56-1.11; six to nine exacerbations, HR = 0.92, 95% CI 0.58-1.46; ≥ 10 exacerbations, HR = 1.16, 95% CI 0.75-1.81)., Conclusions: CF-related diabetes is a significant risk factor for chronic kidney disease in adults with CF, but additional studies examining IV aminoglycoside exposure directly are required.

Rationale: Sputum biomarkers of infection and inflammation are noninvasive measures that enable quantification of the complex pathophysiology of cystic fibrosis (CF) lung disease. Validation of these biomarkers as correlates of disease severity is a key step for their application., Objectives: We constructed a large database from four multicenter studies to quantify the strength of association between expectorated sputum biomarkers and FEV(1.), Methods: FEV(1) (range, 25-120% predicted) and quantitative data on expectorated sputum biomarkers including free neutrophil elastase, IL-8, neutrophils, Pseudomonas aeruginosa, and Staphylococcus aureus were obtained from 269 participants (ages, 9-54 years) from 33 centers. Cross-sectional and longitudinal statistical analyses were performed to estimate associations between the markers and FEV(1), including the use of multivariable analyses., Results: Elastase was negatively correlated with FEV(1) (correlation [r] = -0.35; 95% confidence interval [CI]: -0.46, -0.22). On average, patients with CF who differed in their elastase measurements by 0.5 log differed in their FEV(1) values by -7.3% (95% CI: -9.7, -4.6). Neutrophil counts and IL-8 were also each negatively correlated. In a multivariable regression, elastase and neutrophil counts were able to explain the majority of variation in FEV(1). Elastase was further shown to have a significant longitudinal association with FEV(1), specifically a -2.9% decline in FEV(1) (95% CI: -5.0, -0.9) per 1-log increase in elastase. Although correlated with FEV(1), bacterial densities were unable to explain clinically meaningful differences in FEV(1) within and across patients., Conclusions: These data support the role of sputum biomarkers as correlates of disease severity in a diverse CF population.

Rationale: We recently reported a randomized, placebo-controlled trial of azithromycin in patients with cystic fibrosis (CF) that demonstrated a 6.2% improvement in the 168-d relative change in FEV1 among azithromycin participants compared with placebo participants., Objectives: In the current analyses, heterogeneity of treatment response and the association between FEV1 and the risk of pulmonary exacerbations were investigated., Methods: The time to first pulmonary exacerbation, hospitalization rates, and antibiotic use were compared between participants categorized by their relative change in FEV1 % predicted (>or= 5 vs. < 5% improvement) at Day 168. Pulmonary function and exacerbation responses were compared in subgroups of participants characterized by long-term concomitant medications and baseline lung function., Measurements: All available data from the 185 randomized participants in the azithromycin trial were included in these analyses., Main Results: Compared with placebo participants, a reduced risk of pulmonary exacerbations was observed both among azithromycin participants with >or= 5% and those with < 5% relative improvement in FEV1. Similarly, decreased hospitalization rates and decreased use of oral quinolone and nonquinolone antibiotics were observed in azithromycin participants regardless of improvement in FEV1. Subgroup analyses demonstrated that overall, participants on long-term aerosolized tobramycin and/or rhDNase had worse baseline lung function, but still benefited from azithromycin, as evidenced by a lower risk of exacerbations., Conclusions: Azithromycin participants experienced benefits in exacerbation parameters regardless of FEV1 response or subgroup. These data have implications for clinical practice and the design of clinical trials.

Induced sputum has been used to study airway inflammation. We sought to determine whether markers of infection and inflammation in induced sputum were a useful and safe outcome measure in cystic fibrosis. We hypothesized that bacterial density and inflammatory content of induced sputum would decrease after antibiotic therapy. Induced sputum was assayed for bacterial density, cell count, and differential and inflammatory markers before and after treatment with intravenous antibiotics. Fifty-five of the 72 subjects enrolled (mean age +/- SD 18.2 +/- 7.9 years) completed the study. FEV1 increased by an average 0.3 +/- 0.3 L (10.4 +/- 8.7% predicted FEV1), p<0.0001; density of Pseudomonas aeruginosa and Staphylococcus aureus decreased by 2.4 +/- 3.1 log10 cfu/g (p<0.0005) and 4.0 +/- 2.3 log10 cfu/ml (p<0.0001), respectively; neutrophil count decreased by 0.4 +/- 0.6 log10 cells/ml (p<0.0001), interleukin-8 concentration by 0.5 +/- 1.3 log10 pg/ml (p<0.05), and neutrophil elastase by 0.4 +/- 0.7 log10 microg/ml (p<0.005). Seven of 127 (6%) sputum induction procedures showed a decrease in FEV1 of 20% or more. We conclude that markers in induced sputum may be useful, noninvasive outcome measures to assess response to therapies in cystic fibrosis studies.

The first objective of our study was to develop a model identifying the best clinical predictors of 2-year mortality among patients with cystic fibrosis (CF), to assist in selection of appropriate candidates for lung transplantation. Using multivariate logistic regression, we found that age, height, FEV1, respiratory microbiology, number of hospitalizations for pulmonary exacerbations, and number of home intravenous antibiotic courses were all significant predictors of 2-year mortality among 14,572 patients in the Cystic Fibrosis Foundation National Patient Registry who were 6 years of age or older in 1996. The second objective was to compare the diagnostic accuracy of our model when used to guide referral for lung transplant with that of the widely used criterion of an FEV1 of less than 30% predicted. Surprisingly, this well-fitting model derived from the largest collection of data available on patients with CF provided no better diagnostic accuracy than the simpler FEV1 criterion. Both had high negative predictive values (98 and 97%, respectively) but only modest positive predictive values (33 and 28%, respectively). Transplant referral decisions based either on a multivariate logistic model or on the criterion of an FEV1 of less than 30% predicted are likely to result in high rates of premature referral. Better clinical predictors of short-term mortality among patients with CF are needed.