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Summary Background Infection is a key component of bronchiectasis pathophysiology. Characterisation of the microbiome offers a higher degree of sensitivity and resolution than does traditional culture methods. We aimed to evaluate the role of the microbiome in determining the risk of exacerbation and long-term outcomes, including all-cause mortality, in bronchiectasis. Methods We did a prospective observational cohort study of patients with bronchiectasis from eastern Scotland. Patients were enrolled from Sept 11, 2012, to Dec 21, 2015, and followed until Jan 8, 2019, for long-term outcomes. Patients were included if they were aged 18 years or older, and had a high-resolution CT-confirmed diagnosis of bronchiectasis and clinical symptoms consistent with the disease. Sputum samples were obtained when patients were clinically stable. Repeat sputum samples were taken at stable and exacerbation visits during follow-up. The V3–V4 region of the bacterial 16S rRNA gene was sequenced using the Illumina MiSeq platform. The dominant bacterial genus in each sample was assigned on the basis of a previously published method. Microbiome characteristics were analysed for their association with measures of clinical disease severity and long-term outcomes using PERMANOVA, random forest, and survival analyses. Findings Sequencing data were obtained from the sputum samples of 281 patients with bronchiectasis who were included in the stable baseline cohort. 49 (17%) of 281 patients provided more than one sample when clinically stable and were included in the longitudinal analysis. 64 (23%) patients provided both stable and exacerbation samples. In both stable bronchiectasis and during exacerbations, a sputum microbiome dominated by Proteobacteria and Firmicutes was observed. Individual patients' microbiome profiles were relatively stable over time, during exacerbations and at disease stability. Lower microbiome diversity, measured using the Shannon-Wiener diversity index, was associated with more severe bronchiectasis defined by the bronchiectasis severity index, lower FEV1, and more severe symptoms. Random forest analysis of baseline samples identified Pseudomonas, Enterobacteriaceae, and Stenotrophomonas as being associated with severe bronchiectasis (bronchiectasis severity index ≥9) and greater lung inflammation and Pseudomonas and Enterobacteriaceae with more frequent exacerbations. Patients in whom Pseudomonas was dominant (n=35) were at increased risk of all-cause mortality (hazard ratio 3·12, 95% CI 1·33–7·36; p=0·0091) and had more frequent exacerbations (incident rate ratio 1·69, 95% CI 1·07–2·67; p=0·024) during follow-up compared with patients with other dominant genera (n=246). Interpretation A reduction in microbiome diversity, particularly one associated with dominance of Pseudomonas, is associated with greater disease severity, higher frequency and severity of exacerbations, and higher risk of mortality. The microbiome might therefore identify subgroups of patients at increased risk of poor outcomes who could benefit from precision treatment strategies. Further research is required to identify the mechanisms of reduced microbiome diversity and to establish whether the microbiome can be therapeutically targeted. Funding British Lung Foundation and European Respiratory Society EMBARC2 consortium.

Rationale: Bronchiectasis guidelines regard treatment to prevent exacerbation and treatment of daily symptoms as separate objectives.Objectives: We hypothesized that patients with greater symptoms ...

Background Pulmonary rehabilitation improves exercise capacity and reduces risk of future exacerbation in COPD when performed after an exacerbation. There have been no previous studies of post-exacerbation rehabilitation in bronchiectasis. Methods Parallel group randomized controlled trial compared pulmonary rehabilitation (PR) to standard care (SC) in patients followed an antibiotic treated exacerbation of bronchiectasis. Patients were randomized following a 14 day course of antibiotics was completed. The primary outcome was 6-min walk distance (6 MW) at 8 weeks. Secondary outcomes were time to the next exacerbation, St.Georges Respiratory Questionnaire, COPD CAT score, Leicester cough questionnaire (LCQ) and FEV1 at 8 and 12 weeks post exacerbation. Results Forty eight patients were enrolled but only 27 had exacerbations within 12 months of enrolment. Nine patients received pulmonary rehabilitation and 18 received standard care. The 6 MW improved significantly from post-exacerbation to 8 weeks in both groups, with no significant difference between PR and SC- mean difference of 11 m (95% CI -34.3 to 56.3,p = 0.6). Time to the next exacerbation was not significantly different hazard ratio 0.83 (0.31–2.19, p = 0.7). No significant differences were seen between groups in terms of LCQ, CAT, FEV1 or SGRQ between groups. An analysis of probability based on the patients enrolled suggested > 1000 subjects are likely be required to have an > 80% probability of observing a statistically significant difference between PR and SC and any such differences would be likely to be too small to be clinically relevant. Conclusions This pilot study identified no significant benefits associated with pulmonary rehabilitation after exacerbations of bronchiectasis. Trial registration NCT02179983, registered on Clinicaltrials.gov 29th June 2014.

Background: Randomized Trials in bronchiectasis may have been underpowered due to unexpectedly large “placebo effects”. We used a combination of meta-analysis and analysis of the European Bronchiectasis Registry (EMBARC) to quantify “placebo effects” in randomized trials in bronchiectasis Method: We searched electronic databases from 1990-2019, to identify double blind, randomized, placebo-controlled trials of drug treatment in bronchiectasis. We defined the “placebo effects” by comparing the outcomes at the end of placebo treatment and at baseline prior to treatment. EMBARC registry data were employed to model changes in exacerbation rate and quality of life (QoL) Result: 27 trials were included for meta-analysis (N=1739 placebo-treated patients). Placebo treatment was associated with significantly reduced exacerbation rate (mean difference [MD] -1.79, -2.03 to -1.56; p Conclusion: Placebo treatment was associated with improved QoL and reduced exacerbation in bronchiectasis. Enrolling patients with 1 or more exacerbation may be an optimal inclusion criteria

Background: Bronchiectasis guidelines regard treatment to prevent exacerbation and relieve symptom as separate objective. We hypothesized that patients with greater symptoms would be at higher risk of exacerbation and therefore a treatment aimed at reducing symptoms would reduce exacerbations in highly symptomatic patients. Methods: An observational cohort of 333 patients are analyzed. Symptoms were either modelled as a continuous variable or patients were classified as high, moderate and low symptom burden (>70, 40-70 and Results: In the observational cohort symptoms were a significant predictor of future exacerbations (rate ratio [RR] 1.10, 95% confidence interval [CI] 1.03-1.17, P=0.005). Patients with high symptom scores had higher exacerbation rates (RR 1.74, 95% CI 1.12-2.72, P=0.01) over 12 months follow-up compared to those with low symptoms. Inhaled mannitol improved the time to first exacerbation (hazard ratio 0.56; 95% CI 0.40-0.77; P Conclusions: Highly symptomatic patients are at increased risk of exacerbations and have exacerbation benefit with inhaled mannitol.

Background: The MUSIC study is testing the impact of inhaled corticosteroid (ICS) and bronchodilator (LABA/LAMA) treatment on the upper and lower airway microbiome in patients with COPD (NCT02972476). Patients receiving ICS at baseline withdrew therapy for one month, followed by randomization to 3 different ICS regimes or combined LABA/LAMA for 3 months. Here we report rates of patients experiencing exacerbations during the withdrawal period Methods: Multicentre randomized controlled trial. Patients were aged >=40 years, current or exsmokers, FEV1/FVC Results: 122 patients were enrolled from 6 study sites. 52.5% of patients were male, mean age 67 years (standard deviation(SD) 8.1), and mean post-bronchodilator FEV1 54.9% predicted (SD 20.7). 48 patients had blood eosinophil counts 300cells/ul (18.0%). 57 patients experienced an exacerbation or adverse event leading to withdrawal during month 1., Rates of failure ranged from 42-69% with no differences between sites (p=0.52). Failure rates were 56.3% in low, 46.2% in moderate, 45.5% in high eosinophil groups (p=0.54). Failure rates were significantly higher in patients with FEV1 50% (41.8%), (odds ratio 2.23 95% CI 1.06 – 4.67,p=0.034). Conclusion: We found a high failure rate during 1 month switch to LABA/LAMA, particularly in patients with severe and very severe lung function impairment.

Summary Background Bronchiectasis is predominantly a neutrophilic inflammatory disease. There are no established therapies that directly target neutrophilic inflammation because little is understood of the underlying mechanisms leading to severe disease. Neutrophil extracellular trap (NET) formation is a method of host defence that has been implicated in multiple inflammatory diseases. We aimed to investigate the role of NETs in disease severity and treatment response in bronchiectasis. Methods In this observational study, we did a series of UK and international studies to investigate the role of NETs in disease severity and treatment response in bronchiectasis. First, we used liquid chromatography-tandem mass spectrometry to identify proteomic biomarkers associated with disease severity, defined using the bronchiectasis severity index, in patients with bronchiectasis (n=40) in Dundee, UK. Second, we validated these biomarkers in two cohorts of patients with bronchiectasis, the first comprising 175 patients from the TAYBRIDGE study in the UK and the second comprising 275 patients from the BRIDGE cohort study from centres in Italy, Spain, and UK, using an immunoassay to measure NETs. Third, we investigated whether pathogenic bacteria had a role in NET concentrations in patients with severe bronchiectasis. In a separate study, we enrolled patients with acute exacerbations of bronchiectasis (n=20) in Dundee, treated with intravenous antibiotics for 14 days and proteomics were used to identify proteins associated with treatment response. Findings from this cohort were validated in an independent cohort of patients who were admitted to the same hospital (n=20). Fourth, to assess the potential use of macrolides to reduce NETs in patients with bronchiectasis, we examined two studies of long-term macrolide treatment, one in patients with bronchiectasis (n=52 from the UK) in which patients were given 250 mg of azithromycin three times a week for a year, and a post-hoc analysis of the Australian AMAZES trial in patients with asthma (n=47) who were given 500 mg of azithromycin 3 times per week for a year. Findings Sputum proteomics identified that NET-associated proteins were the most abundant and were the proteins most strongly associated with disease severity. This finding was validated in two observational cohorts, in which sputum NETs were associated with bronchiectasis severity index, quality of life, future risk of hospital admission, and mortality. In a subgroup of 20 patients with acute exacerbations, clinical response to intravenous antibiotic treatment was associated with successfully reducing NETs in sputum. Patients with Pseudomonas aeruginosa infection had a lessened proteomic and clinical response to intravenous antibiotic treatment compared with those without Pseudomonas infections, but responded to macrolide therapy. Treatment with low dose azithromycin was associated with a significant reduction in NETs in sputum over 12 months in both bronchiectasis and asthma. Interpretation We identified NETs as a key marker of disease severity and treatment response in bronchiectasis. These data support the concept of targeting neutrophilic inflammation with existing and novel therapies. Funding Scottish Government, British Lung Foundation, and European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC).

Background Identifying patients with COPD at increased risk of poor outcomes is challenging due to disease heterogeneity. Potential biomarkers need to be readily available in real-life clinical practice. Blood eosinophil counts are widely studied but few studies have examined the prognostic value of blood neutrophil counts (BNC). Methods In a large population-based COPD registry in the East of Scotland (TARDIS: Tayside Allergic and Respiratory Disease Information System), BNC were compared to measures of disease severity and mortality for up to 15 years follow-up. Potential mechanisms of disease modification by BNC were explored in a nested microbiome substudy. Results 178,120 neutrophil counts were obtained from 7220 people (mean follow up 9 years) during stable disease periods. Median BNC was 5200cells/μL (IQR 4000-7000cells/μL). Mortality rates among the 34% of patients with elevated BNCs (defined as 6000-15000cells/μL) at the study start were 80% higher (14.0/100 person years v 7.8/100py, P P N = 276), patients with elevated BNC had increased relative abundance of Proteobacteria and reduced microbiome diversity. Conclusion High BNC may provide a useful indicator of risk of exacerbations and mortality in COPD patients.

Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of "at-risk" first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several SDHA alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening.

IntroductionTo identify risk factors, absolute risk, and impact on treatment discontinuation of genital infections with sodium-glucose co-transporter-2 inhibitors (SGLT2i).Research design and methodsWe assessed the relationship between baseline characteristics and genital infection in 21 004 people with type 2 diabetes initiating SGLT2i and 55 471 controls initiating dipeptidyl peptidase-4 inhibitors (DPP4i) in a UK primary care database. We assessed absolute risk of infection in those with key risk factors and the association between early genital infection and treatment discontinuation.ResultsGenital infection was substantially more common in those treated with SGLT2i (8.1% within 1 year) than DPP4i (1.8%). Key predictors of infection with SGLT2i were female sex (HR 3.64; 95% CI 3.23 to 4.11) and history of genital infection; 5 years (HR 1.79; 1.55 to 2.07). Baseline HbA1c was not associated with infection risk for SGLT2i, in contrast to DPP4i where risk increased with higher HbA1c. One-year absolute risk of genital infection with SGLT2i was highest for those with a history of prior infection (females 23.7%, males 12.1%), compared with those without (females 10.8%, males 2.7%). Early genital infection was associated with a similar discontinuation risk for SGLT2i (HR 1.48; 1.21–1.80) and DPP4i (HR 1.58; 1.21–2.07).ConclusionsFemale sex and history of prior infection are simple features that can identify subgroups at greatly increased risk of genital infections with SGLT2i therapy. These data can be used to risk-stratify patients. High HbA1c is not a risk factor for genital infections with SGLT2i.

Background: Bronchiectasis is predominantly a neutrophilic inflammatory disease. There are no established therapies that directly target neutrophilic inflammation because of a lack of understanding of the underlying mechanisms leading to severe disease. Neutrophil extracellular trap (NET) formation is a mode of host defence that has been implicated in multiple inflammatory diseases. Methods: We conducted a series of UK and international studies to investigate the role of NETs in disease severity and treatment response in bronchiectasis. Nano LC/MS-MS was used to identify proteomic markers associated with disease severity, defined using the bronchiectasis severity index (BSI) (n=40). These were validated in two cohorts (n=175 and n=275) using a validated immunoassay to measure NETs. 20 patients with acute exacerbations of bronchiectasis were treated with intravenous antibiotics for 14 days and proteomics used to identify proteins associated with treatment response. Two studies of long-term macrolide treatment, one in bronchiectasis and a post-hoc analysis of the AMAZES trial in asthma, investigated the effect of macrolide treatment on NETs. Findings: 96 proteins were differentially expressed in sputum between severe and mild bronchiectasis. The most abundant and most discriminating were proteins known to be NET proteins. This was validated in two observational cohorts where sputum NETs were associated with BSI, quality of life, lung function, future risk of hospital admissions and mortality. Antibiotic treatment in 20 patients was associated with 23 significantly down-regulated and 16 up-regulated proteins, with the “neutrophil degranulation” pathway being most strongly implicated in response. Patients with Pseudomonas aeruginosa infection had a blunted proteomic and clinical response to treatment. Treatment with low dose azithromycin was associated with a significant reduction in NETs in sputum over 12 months in both bronchiectasis and asthma. Interpretation: NETs are identified as a key marker of disease severity and treatment response in bronchiectasis. Funding: Supported by the Scottish Government Chief Scientist Office (Senior Clinical Fellowship to JDC) and British Lung Foundation through the BLF Chair of Respiratory Research. Supported by the European Bronchiectasis Network (EMBARC), a European Respiratory Society Clinical Research Collaboration. Declaration of Interests: None to declare Ethics Approval Statement: The studies were approved by local research ethics committees and patients provided informed consent.

Background The sputum microbiome has a potential role in disease phenotyping and risk stratification in chronic obstructive pulmonary disease (COPD), but few large longitudinal cohort studies exist. Objective Our aim was to investigate the COPD sputum microbiome and its association with inflammatory phenotypes and mortality. Methods 16S ribosomal RNA gene sequencing was performed on sputum from 253 clinically stable COPD patients (4-year median follow-up). Samples were classified as Proteobacteria or Firmicutes (phylum level) and Haemophilus or Streptococcus (genus level) dominant. Alpha diversity was measured by using Shannon-Wiener diversity and Berger-Parker dominance indices. Survival was modeled by using Cox proportional hazards regression. A subset of 78 patients had label-free liquid chromatography with tandem mass spectrometry performed, with partial least square discriminant analysis integrating clinical, microbiome, and proteomics data. Results Proteobacteria dominance and lower diversity was associated with more severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease classification system (P = .0015), more frequent exacerbations (P = .0042), blood eosinophil level less than or equal to 100 cells/μL (P Conclusion The sputum microbiome is associated with clinical and inflammatory phenotypes in COPD. Reduced microbiome diversity, associated with Proteobacteria (predominantly Haemophilus) dominance, is associated with neutrophil-associated protein profiles and an increased risk of mortality.

Background: Bronchiectasis (BE) guidelines recommend long term macrolide treatment for patients with ≥3 exacerbations/year without P aeruginosa infection. Randomized controlled trials (RCTs) suggest that long term macrolide treatment can prevent exacerbations in adult patients with BE but these studies have been too small to conduct meaningful subgroup analyses. Aims: To explore macrolide benefit in subpopulations, including those where macrolide therapy is not currently recommended, using individual patient data (IPD) meta-analysis. Methods: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched to identify RCT’s of macrolide antibiotics for at least 3 months with a primary outcome of BE exacerbations. IPD meta-analysis was performed using fixed effects models adjusting for age, sex, FEV1 and trial. Results: IPD was obtained for 341 participants in 3 RCTs. Macrolides reduced the frequency of exacerbations adjusted incidence rate ratio (IRR) 0.49 95% CI 0.36-0.66,p Conclusions: Long-term macrolide treatment significantly reduces the rate of exacerbations in patients with BE with similar benefits observed in all subgroups based on patient characteristics.

Introduction: Bronchiectasis and COPD are two disease entities with overlapped clinical features but whether underlying biology supports a “treatable traits” approach is unknown. Aim: To investigate the endotypic differences in sputum microbiome and proteome between patients with BE, COPD, and the overlap. Methods: Patients with BE (n=61, age 72±8 years, FEV1(pred) 85±23), COPD (n=56, age 72±9 years, FEV1(pred) 67±22%), and the overlap (n=63, age 72±8 years, FEV1(pred) 66±24%) were included. Sputum microbiome and protein profiling were carried out using 16S rRNA sequencing and a label-free proteomics workflow, respectively. Results: Principle component analysis of combined sputum microbiome (1,393 OTUs) and proteome profiles (614 proteins) revealed two clusters that partially separate COPD patients with BE from those without (Figure). COPD patients with BE were co-clustered with patients with BE. Patients with BE (regardless of COPD status) were predominantly associated with a proteobacteria dominant microbiome profile and a proteome profile over-represented with the “neutrophil degranulation” pathway (over-representation p=8E-13). In contrast, COPD patients without BE displayed a higher microbiome diversity, a firmicutes dominant microbiome profile and higher expression of IGK, PIGR, AZGP1 and TCN1. Conclusion: Independent of COPD status, BE is a dominant trait associated with a proteobacteria and neutrophilic endotype.

Introduction: COPD is a heterogenous disease which makes identifying patients more likely to respond to a particular treatment or at higher risk of poor clinical outcomes challenging. Methods: Microbiome characterization by 16S bacterial rRNA gene sequencing was performed on sputum samples obtained from 297 COPD patients studied during stable disease with a median follow up of 4 years. Samples were classified at the phyla level as proteobacteria or firmicutes dominant whilst at the genera level samples were classed as Haemophilus or Streptococcus dominant. If no phyla or genera was represented at greater than 40% these were classed as “balanced microbiomes”. The results were compared to clinical characteristics to determine the utility of stable disease microbiome in predicting outcomes. Results: Proteobacteria dysbiosis and loss of microbiota diversity (Shannon-Wiener Diversity Index) was associated with more severe COPD by GOLD stage (P=0.0007), more frequent prior exacerbations (P=0.0057), low blood eosinophil counts ( Proteobacteria dysbiosis was associated with an increased risk of mortality (HR 2.39 95% CI 1.23-4.66, p=0.01) compared to those with a balanced or firmicutes dominated microbiome. Uniquely among Firmicutes, patients with a Streptococcus dominated microbiome had an increased mortality risk (HR 2.58 95% CI 1.03-6.46, p= 0.043) when compared to those with balanced microbiomes. Conclusions: Reduced microbiome diversity, driven by Proteobacteria (predominantly Haemophilus) or Streptococcus dysbiosis is associated with increased mortality and may indicate COPD endotypes at increased risk of negative outcomes. Funder: GSK

Rationale: The principal underlying inhaled antibiotic treatment in bronchiectasis is that airway bacterial load drives inflammation, and therefore antibiotic treatment will reduce symptoms. Objectives: To determine the relationship between bacterial load and clinical outcomes, assess the stability of bacterial load over time, and test the hypothesis that response to inhaled antibiotics would be predicted by baseline bacterial load. Methods: We performed three studies. Studies 1 and 2 were prospective studies including adults with bronchiectasis. Study 3 was a post hoc analysis of a randomized trial of inhaled aztreonam. A priori patients were divided into low (= 10(7) cfu/g) using quantitative sputum culture. Measurements and Main Results: Bacterial load was a stable trait associated with worse quality of life and more airway inflammation in studies 1, 2, and 3. In study 3, patients with high bacterial load showed an improvement in the primary endpoint (Quality of Life-Bronchiectasis-Respiratory Symptoms Score at Week 4) in favor of aztreonam (mean difference of 9.7 points; 95% confidence interval, 3.4-16.0; P = 0.003). The proportion of patients who achieved an increase above the minimum clinically important difference was higher in the aztreonam group at Week 4 (63% vs. 37%; P = 0.01) and at Week 12 (62% vs. 38%; P = 0.01) only in high bacterial load patients. Conclusions: Improvement of quality of life with inhaled aztreonam was only evident in patients with high bacterial load. Bacterial load may be a useful biomarker of severity of disease and treatment response.

Background: Bronchiectasis guidelines recommend long-term macrolide treatment for patients with three or more exacerbations per year without Pseudomonas aeruginosa infection. Randomised controlled trials suggest that long-term macrolide treatment can prevent exacerbations in adult patients with bronchiectasis, but these individual studies have been too small to do meaningful subgroup analyses. We did a systematic review and individual patient data (IPD) meta-analysis to explore macrolide benefit in subpopulations, including those in which macrolide therapy is not currently recommended. Methods: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science from Jan 1, 2000, to Sept 30, 2018, to identify double blind, randomised, placebo-controlled trials of macrolide antibiotics in adult patients with bronchiectasis. We applied no language restrictions. Randomised controlled trials were eligible if treatment was defined a priori as long term and had a primary or secondary outcome of bronchiectasis exacerbations. Studies in patients with cystic fibrosis bronchiectasis were excluded. The primary outcome of the meta-analysis was frequency of exacerbations requiring treatment with antibiotics. Secondary endpoints were time to first exacerbation, change in quality of life according to the St George's Respiratory Questionnaire (SGRQ), and change in FEV1. IPD meta-analysis was done using fixed effects models adjusting for age, sex, FEV1, and trial. We did prespecified subgroup analyses for each of the primary and secondary endpoints using one-step meta-analysis only. Subgroups were defined by age, sex, previous exacerbation frequency, smoking status, inhaled corticosteroid use at baseline, body-mass index at baseline, cause, C-reactive protein at baseline, baseline FEV1 percentage of predicted, SGRQ total score, and Pseudomonas aeruginosa in sputum culture at baseline. The meta-analysis is registered with the PROSPERO international register of systematic reviews, number CRD42018102908. Findings: Of 234 identified studies, we included three randomised controlled trials, and IPD was obtained for 341 participants. Macrolide antibiotics reduced the frequency of exacerbations (adjusted incidence rate ratio [IRR] 0·49, 95% CI 0·36 to 0·66; p

Introduction: Infection is a key component of the pathophysiology of bronchiectasis. Characterisation of the microbiome offers a higher degree of sensitivity and resolution than traditional culture to evaluate the importance of infection in determining the risk of exacerbation and long-term outcomes, including mortality, in bronchiectasis. Methods: Sputum samples from 281 patients with bronchiectasis included in a longitudinal cohort of patients from two hospitals in the East of Scotland underwent 16S rRNA amplicon sequencing. Sputum supernatant was used to measure neutrophil elastase activity by immunoassay. Patients were enrolled from 2012-2015 and followed up until January 2019 for long term outcomes. Repeat sputum samples were obtained at exacerbation and stable visits during follow-up. Dominant genera was assigned based on a previously published method. Microbiome characteristics were compared to measures of clinical disease severity and long term outcomes. Results: In both stable bronchiectasis and during exacerbations, a microbiome dominated by Proteobacteria and Firmicutes was observed. Beta diversity analysis indicated that patients' microbiomes were relatively stable over time and showed less variation than that observed between patients. During disease stability, reduced Shannon-Wiener Diversity Index was associated with higher bronchiectasis severity (P

IntroductionInhaled antibiotics may improve symptom scores, but it is not known which specific symptoms improve with therapy. Item-level analysis of questionnaire data may allow us to identify which specific symptoms respond best to treatment.MethodsPost hoc analysis of the AIR-BX1 studies and two trials of inhaled aztreonam versus placebo in bronchiectasis. Individual items from the quality of life bronchiectasis (QOL-B) respiratory symptom scale, were extracted as representing severity of nine distinct symptoms. Generalised linear models were used to evaluate changes in symptoms with treatment versus placebo from baseline to end of first on-treatment cycle and mixed models were used to evaluate changes across the full 16-week trial.ResultsAztreonam improved cough (difference 0.22, 95% CI 0.08–0.37; p=0.002), sputum production (0.30, 95% CI 0.15–0.44; pversus placebo equating to a 20% improvement in cough and 25% improvement in sputum production and colour. Similar results were observed for cough, sputum production and sputum purulence across the trial duration (all pConclusionBaseline bronchitic symptoms predict response to inhaled aztreonam in bronchiectasis. More sensitive tools to measure bronchitic symptoms may be useful to better identify inhaled antibiotic responders and to evaluate patient response to treatment.

OBJECTIVEThe impact of taking oral glucose-lowering medicines intermittently, rather than as recommended, is unclear. We conducted a retrospective cohort study using community-acquired U.K. clinical data (Clinical Practice Research Database [CPRD] and GoDARTS database) to examine the prevalence of nonadherence to treatment for type 2 diabetes and investigate its potential impact on HbA1c reduction stratified by type of glucose-lowering medication.RESEARCH DESIGN AND METHODSData were extracted for patients treated between 2004 and 2014 who were newly prescribed metformin, sulfonylurea, thiazolidinedione, or dipeptidyl peptidase 4 inhibitors and who continued to obtain prescriptions over 1 year. Cohorts were defined by prescribed medication type, and good adherence was defined as a medication possession ratio ≥0.8. Linear regression was used to determine potential associations between adherence and 1-year baseline-adjusted HbA1c reduction.RESULTSIn CPRD and GoDARTS, 13% and 15% of patients, respectively, were nonadherent. Proportions of nonadherent patients varied by the oral glucose-lowering treatment prescribed (range 8.6% [thiazolidinedione] to 18.8% [metformin]). Nonadherent, compared with adherent, patients had a smaller HbA1c reduction (0.4% [4.4 mmol/mol] and 0.46% [5.0 mmol/mol] for CPRD and GoDARTs, respectively). Difference in HbA1c response for adherent compared with nonadherent patients varied by drug (range 0.38% [4.1 mmol/mol] to 0.75% [8.2 mmol/mol] lower in adherent group). Decreasing levels of adherence were consistently associated with a smaller reduction in HbA1c.CONCLUSIONSReduced medication adherence for commonly used glucose-lowering therapies among patients persisting with treatment is associated with smaller HbA1c reductions compared with those taking treatment as recommended. Differences observed in HbA1c responses to glucose-lowering treatments may be explained in part by their intermittent use.

OBJECTIVE The choice of therapy for type 2 diabetes after metformin is guided by overall estimates of glycemic response and side effects seen in large cohorts. A stratified approach to therapy would aim to improve on this by identifying subgroups of patients whose glycemic response or risk of side effects differs markedly. We assessed whether simple clinical characteristics could identify patients with differing glycemic response and side effects with sulfonylureas and thiazolidinediones. RESEARCH DESIGN AND METHODS We studied 22,379 patients starting sulfonylurea or thiazolidinedione therapy in the U.K. Clinical Practice Research Datalink (CPRD) to identify features associated with increased 1-year HbA1c fall with one therapy class and reduced fall with the second. We then assessed whether prespecified patient subgroups defined by the differential clinical factors showed differing 5-year glycemic response and side effects with sulfonylureas and thiazolidinediones using individual randomized trial data from ADOPT (A Diabetes Outcome Progression Trial) (first-line therapy, n = 2,725) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) (second-line therapy, n = 2,222). Further replication was conducted using routine clinical data from GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) (n = 1,977). RESULTS In CPRD, male sex and lower BMI were associated with greater glycemic response with sulfonylureas and a lesser response with thiazolidinediones (both P < 0.001). In ADOPT and RECORD, nonobese males had a greater overall HbA1c reduction with sulfonylureas than with thiazolidinediones (P < 0.001); in contrast, obese females had a greater HbA1c reduction with thiazolidinediones than with sulfonylureas (P < 0.001). Weight gain and edema risk with thiazolidinediones were greatest in obese females; however, hypoglycemia risk with sulfonylureas was similar across all subgroups. CONCLUSIONS Patient subgroups defined by sex and BMI have different patterns of benefits and risks on thiazolidinedione and sulfonylurea therapy. Subgroup-specific estimates can inform discussion about the choice of therapy after metformin for an individual patient. Our approach using routine and shared trial data provides a framework for future stratification research in type 2 diabetes.

In 1988 and 2002 dramatic and well-documented phocine distemper epizootics occurred in Europe. While their progression and impact were remarkably similar and consistent over much of Europe, mortality in the UK varied greatly between and within the 2 epizootics. We use antibody lev- els in blood samples to show that 51% (Bayesian 95% CI: 41 to 61%) of the individuals alive in 5 UK harbour seal populations at the end of the 1988 epizootic had been exposed to the virus, and that the equivalent figure after the 2002 outbreak was 22% (95% CI: 16 to 30%). Antibody prevalence was significantly higher in females than males after the 2002 epizootic. Combining these estimates with information on reductions in the numbers of animals observed hauled out during surveys of the Wash, Moray Firth, and Orkney populations and a simple epidemiological model, suggests that the differences between the 2 epizootics were primarily due to a 27% (95% CI: 8 to 43%) fall in R0, the basic reproductive rate of the virus. The large geographic variation in population effects observed within the UK during each epizootic appears to have been mainly due to differences in case mortal- ity, with R0 being remarkably similar in all the populations investigated.

Phocine distemper virus (PDV) may have killed a small number of grey seals Hali- choerus grypus in European waters in 2002, as it was thought to have done in 1988. PDV is known to affect harbour seal population and distribution patterns, but grey seal pup production trends did not correlate consistently with PDV outbreaks. Numbers of known mothers missing from study colonies do not increase in PDV years and pre-weaning pup mortality is similar to that in other years. Pup growth rates are similar in PDV and non-PDV years. Therefore, no direct evidence links PDV out- breaks to changes in grey seal reproductive parameters at the population, colony, or individual level. Investigation of exposure of grey seals to PDV used CDV virus-neutralisation tests on sera collected from breeding seals pre-1988, 1988, 2001 and 2002. No positive sera (≥titre 1:64) were detected prior to 1988. In 1988, 2001 and 2002 the prevalence was 96, 59 and 83%, respectively. In 2001, prevalence in 'old' mothers (of breeding age by 1988, ≥13 yr old) was 63% compared to 0% in 'young' mothers (born after 1989

This paper uses simple mathematical models to examine the long-term dynamic consequences of the 1988 epizootic of phocine distemper virus (PDV) infection in Northern European common seal populations. In a preliminary analysis of single outbreaks of infection deterministic compartmental models are used to estimate feasible ranges for the transmission rate of the infection and the level of disease-induced mortality. These results also indicate that the level of transmission in 1988 was probably sufficient to eradicate the infection throughout the Northern European common seal populations by the end of the first outbreak. An analysis of longer-term infection dynamics, which takes account of the density-dependent recovery of seal population levels, corroborates this finding. It also indicates that a reintroduction of the virus would be unlikely to cause an outbreak on the scale of the 1988 epizootic until the seal population had recovered for at least 10 years. The general ecological implications of these results are discussed.

The UK holds approximately 40% of the European harbour seal population, with the majority found around the coasts of Scotland. Harbour seal populations in the UK have been monitored through a series of repeated aerial surveys of animals hauled out during the annual moult in early August. This moult count is used as a consistent index of population size. Survey methods and frequencies vary. The Scottish and English east coast populations mainly haul out in tidal estuariesand are surveyed annually, using fixed wing aircraft and digital photography. Populations in north and west Scotland often haul out on rocky shores and are surveyed less frequently, using helicopters fitted with thermal imagers. Overall, the most recent minimum estimate of the UK harbour seal population is 24,250 seals of which 19,800 are in Scotland, 3,200 in England and 1,250 in Northern Ireland. The results show that the number of harbour seals in eastern Englandwas increasing before the 1988 and 2002 phocine distemper (PDV) epizootic but has not increased since the end of the 2002 epizootic. There is also evidence of a general decline in most of the large harbour seal colonies around Scotland. The populations along the north and northwest mainland coast were an exception, with numbers appearing to be stable. Between 2001 and 2008, the population in Orkney declined by 67% and Shetland declined by 40%, indicating harbourseals in these areas experienced substantially increased mortality or very low recruitment over this period. The widespread declines, ranging from Shetland to The Wash, suggest that the causes may have been present over a large part of the North Sea and waters off western Scotland.