Objective To identify novel risk factors and corroborate previously identified risk factors for mean annual decline in FEV1 percent predicted in a large, contemporary, U.S. cohort of young cystic fibrosis patients. Methods Retrospective observational study of participants in the EPIC Observational Study, who were Pseudomonas–negative and ≤12 years of age at enrollment in 2004-2006. The associations between potential demographic, clinical and environmental risk factors evaluated during the baseline year and subsequent mean annual decline in FEV1 percent predicted were evaluated using generalized estimating equations. Results The 946 participants in the current analysis were followed for a mean of 6.2 (SD 1.3) years. Mean annual decline in FEV1 % predicted was 1.01% (95% CI 0.85-1.17%). Children with 1 or no F508del mutations had a significantly smaller annual decline in FEV1 compared to F508del homozygotes. In a multivariable model, risk factors during the baseline year associated with a larger subsequent mean annual lung function decline included female gender, frequent or productive cough, low BMI (<66th percentile, median in the cohort), ≥1 pulmonary exacerbation, high FEV1 (≥115% predicted, in the top quartile), and respiratory culture positive for methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus or Stenotrophomonas maltophilia. Conclusions We have identified a range of risk factors for FEV1 decline in a large cohort of young, CF patients who were Pa negative at enrollment, including novel as well as previously identified characteristics. These results could inform the design of a clinical trial in which rate of FEV1 decline is the primary endpoint and identify high-risk groups that may benefit from closer monitoring.

Background/Objectives Pulmonary exacerbations lead to significant morbidity and mortality in patients with cystic fibrosis (CF). National consensus guidelines exist, but few studies report current practice in the treatment and monitoring of pulmonary exacerbations. We aimed to characterize consistency and variability in the inpatient management of CF-related pulmonary exacerbations. We focused on the use of guideline-recommended maintenance therapies, antibiotic selection and treatment regimens, use of systemic corticosteroids, and frequency of lung function testing. We hypothesized that significant variability in these treatment practices exists nationally. Methods Retrospective cross-sectional study of CF patients’ ≤18 years hospitalized for pulmonary exacerbations between July 1st, 2010 and June 30th, 2015 at hospitals within the U.S. Pediatric Health Information System (PHIS) database that are also Cystic Fibrosis Foundation (CFF)-accredited care centers. One exacerbation per patient was randomly selected over the five-year study period. Results From 38 hospitals, 4,827 individual pulmonary exacerbations were examined. Median length of stay was 10.0 days (IQR 6–14.0 days). Significant variation was seen among centers in use of hypertonic saline (11–100%), azithromycin (5–83%), and systemic corticosteroids (3–61%), and in lung function testing frequency. Four different admission antibiotic regimens were used over 10% of the time, and the most commonly used admission antibiotic regimen was two IV antibiotics without additional oral or inhaled antibiotics (30%). Conclusions Significant variation exists in the treatment and monitoring of pulmonary exacerbations across PHIS-participating, CFF-accredited care centers. Results from this study can inform future research working towards standardized inpatient pulmonary exacerbation management to improve CF-care for children and adolescents.

Rationale: Chronic azithromycin is commonly used in cystic fibrosis based on short controlled clinical trials showing reductions in pulmonary exacerbations and improved FEV 1 . Long-term effects are unknown. Objectives: Examine pulmonary outcomes among chronic azithromycin users compared with matched controls over years of use and consider combined azithromycin use in cohorts using chronic inhaled tobramycin or aztreonam. Methods: This retrospective cohort study used the U.S. cystic fibrosis Foundation Patient Registry. Incident chronic azithromycin users were compared with matched controls by FEV 1 % predicted rate of decline and rates of intravenous antibiotic use to treat pulmonary exacerbations. Propensity score methods were utilized to address confounding by indication. Predefined sensitivity analyses based on lung function, Pseudomonas aeruginosa (PA) status, and follow-up time intervals were conducted. Measurements and Main Results: Across 3 years, FEV 1 % predicted per-year decline was nearly 40% less in those with PA using azithromycin compared with matched controls (slopes, −1.53 versus −2.41% predicted per yr; difference: 0.88; 95% confidence interval [CI], 0.30–1.47). This rate of decline did not differ based on azithromycin use in those without PA. Among all cohorts, use of intravenous antibiotics was no different between azithromycin users and controls. Users of inhaled tobramycin and azithromycin had FEV 1 % predicted per-year decline of −0.16 versus nonusers (95% CI, −0.44 to 0.13), whereas users of inhaled aztreonam lysine and azithromycin experienced a mean 0.49% predicted per year slower decline than matched controls (95% CI, −0.11 to 1.10). Conclusions: Results from this study provide additional rationale for chronic azithromycin use in PA-positive patients to reduce lung function decline.

Purpose of review Many pediatric lung diseases are characterized by infection. These infections are generally diagnosed, studied, and treated using standard culture methods to identify “traditional pathogens”. Based on these techniques, healthy lungs have generally been thought to be sterile. However, recent advances in culture-independent microbiological techniques challenge this paradigm by identifying diverse microbes in respiratory specimens (respiratory microbiomes) from both healthy people and those with diverse lung diseases. In addition, growing evidence suggests a link between gastrointestinal microbiomes and inflammatory diseases of various mucosal surfaces, including airways. Recent findings This article reviews the rapidly developing field of respiratory microbiome research, emphasizing recent progress made employing increasingly sophisticated technologies. While many of the relevant studies have focused on adults with cystic fibrosis (CF), recent research has included children and adults with other respiratory diseases, as well as healthy subjects. These studies suggest that even healthy children have airway microbiomes, and that both respiratory and gastrointestinal microbiomes often differ between healthy people and those with different types and severities of airway disease. The causal relationships between microbiomes, disease type and progression, and treatments such as antibiotics must now be defined. Summary The advent of culture-independent microbiological techniques has transformed how we think about the relationship between microbes and airway disease. More research is required to translate these findings to improved therapies and preventive strategies.