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Bronchiectasis is accompanied by chronic bronchial infection that may drive disease progression. However, the evidence base for antibiotic therapy is limited. DNA based methods offer better identification and quantification of microbial constituents of sputum than standard clinical culture and may help inform patient management strategies. Our study objective was to determine the longitudinal variability of the non-cystic fibrosis (CF) bronchiectasis microbiome in sputum with respect to clinical variables. Eighty-five patients with non-CF bronchiectasis and daily sputum production were recruited from outpatient clinics and followed for six months. Monthly sputum samples and clinical measurements were taken, together with additional samples during exacerbations. 16S rRNA gene sequencing of the sputum microbiota was successful for 381 samples from 76 patients and analysed in conjunction with clinical data. Microbial communities were highly individual in composition and stability, usually with limited diversity and often containing multiple pathogens. When compared to DNA sequencing, microbial culture had restricted sensitivity in identifying common pathogens such as Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis. With some exceptions, community characteristics showed poor correlations with clinical features including underlying disease, antibiotic use and exacerbations, with the subject showing the strongest association with community structure. When present, the pathogens mucoid Pseudomonas aeruginosa and Haemophilus influenzae may also shape the structure of the rest of the microbial community. The use of microbial community analysis of sputum added to information from microbial culture. A simple model of exacerbations driven by bacterial overgrowth was not supported, suggesting a need for revision of principles for antibiotic therapy. In individual patients, the management of chronic bronchial infection may be improved by therapy specific to their microbiome, taking into account pathogen load, community stability, and acute and chronic community responses to antibiotics.

Cystic fibrosis (CF) is the one of the most common inherited diseases. It affects around 10,000 people in the UK, and the median survival age is 47. Recent developments making use of longitudinal patient registry data are producing more detailed and relevant information about predicted life expectancy in CF based on current age and clinical measurements. The objective of this study was toconduct an online survey of adults with CF living in the UK using a web-based questionnaire to investigate: (i) if and how they access information on life expectancy; (ii) what they use it for; (iii) if they want more personalised information on life expectancy or the time until other milestones. The survey was advertised through the Cystic Fibrosis Trust using social media. There were 85 respondents, covering men (39%) and women (61%) aged 16-65. 75% had received information on life expectancy either from their CF care team (34%) or other sources (71%), the most common being the Cystic Fibrosis Trust website and research literature. Most people who received information found it to be beneficial and reported using it in a variety of ways, including to plan strategies for maintaining as best health as possible and to psychologically manage current health status. 82% of respondents were interested in more personalised information about their life expectancy, and participants also noted interest in other outcomes, including time to needing transplant or reaching a low level of lung function. Themes arising in text responses included the importance of good communication of information, the difficulty of relating general information to one's own circumstances, and a desire for increased information on factors that impact on survival in CF. As an outcome from this work, research is underway to establish how information on life expectancy can be presented to people with CF in an accessible way.

lung infection in patients with bronchiectasis, a chronic airway disease that is characterized by episodes of exacerbation, is associated with more severe disease and a higher utilization of health-care resources. Inhaled tobramycin solution reduces the number of acute exacerbations in patients with cystic fibrosis (CF)-related bronchiectasis with P aeruginosa infection but remains untested in the treatment of exacerbations in patients with non-CF bronchiectasis. This study tested the effect of adding inhaled tobramycin solution to oral ciprofloxacin (Cip) for the treatment of acute exacerbations of non-CF bronchiectasis in patients with P aeruginosa infection. A double-blind, randomized, active comparator, parallel-design study conducted at 17 study centers (5 in the United Kingdom, and 12 in the United States) compared 2 weeks of therapy with Cip with either an inhaled tobramycin solution or placebo in 53 adults with known P aeruginosa infection who were having acute exacerbations of bronchiectasis. Clinical symptoms, pulmonary function, clinical efficacy, and sputum microbiology were investigated prospectively. An inhaled solution of Cip with tobramycin, compared to placebo, achieved greater microbiological response but no statistically significant difference in clinical efficacy at days 14 or 21. Clinical and microbiological outcomes at the test of cure (ie, the clinical outcome assessment at day 21) were concordant when an inhaled tobramycin solution was added to therapy with Cip and compared to placebo (p = 0.01). Both subject groups had similar overall adverse event rates, but subjects receiving therapy with an inhaled tobramycin solution reported an increased frequency of wheeze (50%; placebo group, 15%). The addition of an inhaled tobramycin solution to therapy with oral Cip for the treatment of acute exacerbations of bronchiectasis due to P aeruginosa improved microbiological outcome and was concordant with clinical outcome; the inability to demonstrate an additional clinical benefit may have been due to emergent wheeze resulting from treatment.

OBJECTIVE: Diabetes is increasingly common in cystic fibrosis, but little information describing its influence on mortality exists. Using national U.K. data, in this study we document diabetes-specific mortality rates, estimate the impact of diabetes on survival, and estimate population-attributable fractions. RESEARCH DESIGN AND METHODS: This retrospective cohort study identified 8,029 individuals aged 0-65 years from the U.K. Cystic Fibrosis Registry (1996-2005). A total of 5,892 patients were included in analyses of mortality rates, and 4,234 were included in analyses of risk factors. We calculated age-adjusted mortality rates using Poisson regression, standardized mortality ratios using the population of England and Wales, and relative risks using proportional hazards modeling. RESULTS: During 17,672 person-years of follow-up, 393 subjects died. The age-adjusted mortality rate was 1.8 per 100 person-years (95% CI 1.6-2.0). The age-adjusted mortality rates per 100 person-years were 2.0 (1.8-2.4) in female subjects and 1.6 (1.4-1.9) in male subjects, and 4.2 (3.4-5.1) in individuals with diabetes vs. 1.5 (1.3-1.7) in those without diabetes. Independent risk factors for death included diabetes (hazard ratio 1.31 [95% CI 1.03-1.67], female sex (1.71 [1.36-2.14]) plus poorer pulmonary function, lower BMI, Burkholderia cepacia infection, absence of Staphylococcus aureus infection, allergic bronchopulmonary aspergillosis, liver disease, prior organ transplantation, and corticosteroid use. CONCLUSIONS: Individuals with cystic fibrosis die earlier if they have diabetes, which, if delayed or better treated, might reasonably extend survival; this hypothesis merits testing.

Background: Airway clearance techniques (ACTs) are integral to cystic fibrosis (CF) management. However, there is no consensus as to which outcome measures (OMs) are best for assessing ACT efficacy. Objectives: To summarise OMs that have been assessed for their clinimetric properties (including validity, feasibility, reliability, and reproducibility) within the context of ACT research in CF. Design and Methods: A systematic review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) standards. Any parallel or cross-over randomised controlled trial (RCT) investigating outcome measures for ACT in the CF population were eligible for inclusion. The search was performed in five medical databases, clinicaltrials.gov, and abstracts from international CF conferences. The authors planned to independently assess study quality and risk of bias using the COnsensus-based Standards for the selection of health status Measurement InstrumeNts (COSMIN) risk of bias checklist with external validity assessment based upon study details (participants and study intervention). Two review authors (GS and MJ) independently screened search results against inclusion criteria, and further data extraction were planned but not required. Results: No completed RCTs from the 187 studies identified met inclusion criteria for the primary or post hoc secondary objective. Two ongoing trials were identified. Discussion and conclusion: This empty systematic review highlights that high-quality RCTs are urgently needed to investigate and validate the clinimetric properties of OMs used to assess ACT efficacy. With the changing demographics of CF combined with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, an accurate assessment of the current benefit of ACT or the effect of ACT withdrawal is a high priority for clinical practice and future research; OMs which have been validated for this purpose are essential. Registration: This systematic review was registered on the PROSPERO database (CRD42020206033).

IntroductionNon-invasive ventilation (NIV) is used in cystic fibrosis (CF) to support airway clearance techniques (ACTs) by augmenting tidal volumes and reducing patient effort. However, the evidence base for this is limited. We hypothesised that NIV, in addition to usual ACT, would increase sputum clearance. In addition, we investigated ease of sputum clearance (EoC), work of breathing (WoB) and NIV tolerability.MethodsAdults with CF (16+ years) at the end of hospitalisation for a pulmonary exacerbation were randomised to a cross-over trial of NIV-supported ACT or ACT alone in two consecutive days. No other changes to standard care were made. The primary outcome was the total 24-hour expectorated sputum wet weight after the intervention. Spirometry was completed pre-treatment and post-treatment. Oxygen saturations were measured pre-treatment, during treatment and post-treatment. EoC and WoB were assessed using Visual Analogue Scale.Results14 subjects completed the study (7 male, mean age 35 [SD 17] years, mean forced expiratory volume in 1 s [FEV1] 49 [20] % predicted). The difference between treatment regimens was −0.98 g sputum (95% CI −11.5 to 9.6, p=0.84) over 24 hours. During treatment oxygen saturations were significantly higher with NIV-supported ACT (mean difference 2.0, 95% CI 0.9 to 2.6, p=0.0004). No other significant differences were found in post-treatment FEV1, EoC, WoB, oxygen saturations or subject preference.ConclusionsThere was no difference in treatment effect between NIV-supported ACT and ACT alone, although the study was underpowered. Oxygen saturations were significantly higher during NIV-supported ACT, but with no effect on post-treatment saturations. NIV was well tolerated.Trial registration numberNCT01885650.

IntroductionAirway clearance techniques (ACTs) are a gold standard of cystic fibrosis management; however, the majority of research evidence for their efficacy is of low standard; often attributed to the lack of sensitivity from outcome measures (OMs) used historically. This randomised controlled trial (RCT) investigates these standard OMs (sputum weight, forced expiratory volume in 1 s) and new OMs (electrical impedance tomography (EIT), multiple breath washout (MBW) and impulse oscillometry (IOS)) to determine the most useful measures of ACT.Methods and analysisThis is a single-centre RCT with crossover design. Participants perform MBW, IOS and spirometry, and then are randomised to either rest or supervised ACT lasting 30–60 min. MBW, IOS and spirometry are repeated immediately afterwards. EIT and sputum are collected during rest/ACT. On a separate day, the OMs are performed with the other intervention. Primary endpoint is difference in change in OMs before and after ACT/rest. Sample size was calculated with 80% power and significance of 5% for each OM (target n=64).Ethics and disseminationEthics approval was gained from the London–Chelsea Research Ethics Committee (reference 16/LO/0995, project ID 154635). Dissemination will involve scientific conference presentation and publication in a peer-reviewed journal.Trial registration numbersISRCTN11220163 and NCT02721498.

BackgroundIvacaftor is the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator demonstrating clinical benefit in patients with cystic fibrosis (CF). As ivacaftor is intended for chronic, lifelong use, understanding long-term effects is important for patients and healthcare providers.ObjectiveThis ongoing, observational, postapproval safety study evaluates clinical outcomes and disease progression in ivacaftor-treated patients using data from the US and the UK CF registries following commercial availability.MethodsAnnual analyses compare ivacaftor-treated and untreated matched comparator patients for: risks of death, transplantation, hospitalisation, pulmonary exacerbation; prevalence of CF-related complications and microorganisms and lung function changes in a subset of patients who initiated ivacaftor in the first year of commercial availability. Results from the 2014 analyses (2 and 3 years following commercial availability in the UK and USA, respectively) are presented here.ResultsAnalyses included 1256 ivacaftor-treated and 6200 comparator patients from the USA and 411 ivacaftor-treated and 2069 comparator patients from the UK. No new safety concerns were identified based on the evaluation of clinical outcomes included in the analyses. As part of safety evaluations, ivacaftor-treated US patients were observed to have significantly lower risks of death (0.6% vs 1.6%, p=0.0110), transplantation (0.2% vs 1.1%, p=0.0017), hospitalisation (27.5% vs 43.1%, p<0.0001) and pulmonary exacerbation (27.8% vs 43.3%, p<0.0001) relative to comparators; trends were similar in the UK. In both registries, ivacaftor-treated patients had a lower prevalence of CF-related complications and select microorganisms and had better preserved lung function.ConclusionsWhile general limitations of observational research apply, analyses revealed favourable results for clinically important outcomes among ivacaftor-treated patients, adding to the growing body of literature supporting disease modification by CFTR modulation with ivacaftor.EU PAS registration numberEUPAS4270

Abstract Rationale Chronic infection with Pseudomonas aeruginosa is associated with an increased exacerbation frequency, a more rapid decline in lung function, and increased mortality in patients with bronchiectasis. Objectives To perform a randomized placebo-controlled study assessing the efficacy and safety of inhaled colistin in patients with bronchiectasis and chronic P. aeruginosa infection. Methods Patients with bronchiectasis and chronic P. aeruginosa infection were enrolled within 21 days of completing a course of antipseudomonal antibiotics for an exacerbation. Participants were randomized to receive colistin (1 million IU; n = 73) or placebo (0.45% saline; n = 71) via the I-neb twice a day, for up to 6 months. Measurements and Main Results The primary endpoint was time to exacerbation. Secondary endpoints included time to exacerbation based on adherence recorded by the I-neb, P. aeruginosa bacterial density, quality of life, and safety parameters. All analyses were on the intention-to-treat population. Median time (25% quartile) to exacerbation was 165 (42) versus 111 (52) days in the colistin and placebo groups, respectively (P = 0.11). In adherent patients (adherence quartiles 2–4), the median time to exacerbation was 168 (65) versus 103 (37) days in the colistin and placebo groups, respectively (P = 0.038). P. aeruginosa density was reduced after 4 (P = 0.001) and 12 weeks (P = 0.008) and the St. George’s Respiratory Questionnaire total score was improved after 26 weeks (P = 0.006) in the colistin versus placebo patients, respectively. There were no safety concerns. Conclusions Although the primary endpoint was not reached, this study shows that inhaled colistin is a safe and effective treatment in adherent patients with bronchiectasis and chronic P. aeruginosa infection. Clinical trial registered with http://www.isrctn.org/ (ISRCTN49790596)

Treatment of cystic fibrosis lung disease has developed from an understanding of the abnormal airway surface liquid resulting from a lack of function of the cystic fibrosis transmembrane regulator protein. Mucus plugging resulting in infection and inflammation leads to airway wall destruction and bronchiectasis. Inhaled therapies have formed the backbone of treatments. In combination with antibiotics delivered direct to the airway, mucoactive drugs, including mucolytics and hyperosmolar agents, are utilised to improve mucociliary clearance to reduce infection and inflammation. Until recently, airway therapies were delivered as nebulisers, but we have now entered the era of dry powder inhalers for treatment of cystic fibrosis lung disease. The theory and practice of these therapies are discussed in this review.