Long-term macrolide antibiotics for the treatment of bronchiectasis in adults:an individual participant data meta-analysis

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<0·0001). We also found that macrolide treatment improved the time to first exacerbation (adjusted hazard ratio 0·46, 0·34 to 0·61; p<0·0001) and was associated with improved quality of life measured by the SGRQ (mean improvement 2·93 points, 0·03 to 5·83; p=0·048). Macrolides were not associated with a significant improvement in FEV1 (67 mL at 1 year, −22 to 112; p=0·14). Effect estimates in prespecified subgroup analyses revealed a reduced frequency of exacerbations in all prespecified subgroups, including a high level of benefit in patients with P aeruginosa infection (IRR 0·36, 0·18–0·72; p=0·0044) and in patients with one to two exacerbations per year (0·37, 0·16–0·88; p=0·025). Studies were rated as low risk of bias across all domains. Interpretation: Long-term macrolide treatment significantly reduces the frequency of exacerbations in patients with bronchiectasis, with similar benefits observed in all subgroups based on patient characteristics. This finding suggests that macrolides might be considered in patients in whom macrolides are not indicated according to the current guidelines, particularly if alternative approaches to reduce exacerbations have been unsuccessful. However, downsides of long-term macrolide treatment must also be taken into account. Funding: European Respiratory Society

Non-tuberculous mycobacterial pulmonary infections

Submitted by Sandra Infurna ([email protected]) on 2019-05-14T13:52:47Z No. of bitstreams: 1 ACC_Caravalho_IOC_2018.pdf: 454431 bytes, checksum: 86468a62313ad15880a6ccff685e3090 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2019-05-14T14:00:46Z (GMT) No. of bitstreams: 1 ACC_Caravalho_IOC_2018.pdf: 454431 bytes, checksum: 86468a62313ad15880a6ccff685e3090 (MD5)Made available in DSpace on 2019-05-14T14:00:46Z (GMT). No. of bitstreams: 1 ACC_Caravalho_IOC_2018.pdf: 454431 bytes, checksum: 86468a62313ad15880a6ccff685e3090 (MD5) Previous issue date: 2018University of Dundee. Hospital and Medical School. Scottish Centre for Respiratory Research. Dundee, United Kingdom.Mayo Clinic College of Medicine. Rochester, MN, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inovações em Terapias, Ensino e Bioprodutos. Rio de Janeiro, RJ, Brasil.Hospital Universitario de Monterrey. Centro de Investigación, Prevención y Tratamiento de Infecciones Respiratorias. Monterrey, Nuevo León UANL, Mexico.Centro Hospitalar Vila Nova de Gaia. Respiratory Department. Espinho, Portugal.Non-tuberculous mycobacterial (NTM) infections are increasingly rapidly worldwide. The reason for this phenomenon is unclear, but may include the ageing population, the increasing use of immunosuppressive drugs, the increasing prevalence of diseases that confer susceptibility to NTM, such as COPD and bronchiectasis, and growing testing for NTM. Awareness of the NTM related diseases is rising but is still suboptimal. Guidelines from the American Thoracic Society and Infectious Diseases Society of America have provided a framework for evaluating disease and evaluating care. Compliance with these guidelines is, however, very poor globally. NTM infections are amongst the most challenging cases that respiratory and infectious diseases physicians face. The challenges include intrinsic antibiotic resistance, complex drug regimens, poor tolerability and significant side effects associated with therapy and poor response rates. The decision to initiate treatment is therefore often difficult and requires careful evaluation of benefits and risks. Optimal management of NTM infections requires multidisciplinary care with close collaboration between physicians, microbiologists, physiotherapist/allied health professionals, primary care physicians and the patient. There remains a need for greater research into the epidemiology, clinical evaluation and treatment of NTM pulmonary disease. Randomised clinical trials are now being conducted which may provide useful data on the effectiveness of some new and existing therapies. In this review, we discuss the growing importance of NTM pulmonary disease and the opportunities for progress in clinical research for these conditions

Solving the measurement problem: de Broglie-Bohm loses out to Everett

The quantum theory of de Broglie and Bohm solves the measurement problem, but the hypothetical corpuscles play no role in the argument. The solution finds a more natural home in the Everett interpretation.Comment: 20 pages; submitted to special issue of Foundations of Physics, in honour of James T. Cushin

Levels: Descriptive, Explanatory, and Ontological

Scientists and philosophers frequently speak about levels of description, levels of explanation, and ontological levels. In this paper, I propose a unified framework for modelling levels. I give a general definition of a system of levels and show that it can accommodate descriptive, explanatory, and ontological notions of levels. I further illustrate the usefulness of this framework by applying it to some salient philosophical questions: (1) Is there a linear hierarchy of levels, with a fundamental level at the bottom? And what does the answer to this question imply for physicalism, the thesis that everything supervenes on the physical? (2) Are there emergent properties? (3) Are higher-level descriptions reducible to lower-level ones? (4) Can the relationship between normative and non-normative domains be viewed as one involving levels? Although I use the terminology of “levels”, the proposed framework can also represent “scales”, “domains”, or “subject matters”, where these are not linearly but only partially ordered by relations of supervenience or inclusion

The twilight of the Liberal Social Contract? On the Reception of Rawlsian Political Liberalism

This chapter discusses the Rawlsian project of public reason, or public justification-based 'political' liberalism, and its reception. After a brief philosophical rather than philological reconstruction of the project, the chapter revolves around a distinction between idealist and realist responses to it. Focusing on political liberalism’s critical reception illuminates an overarching question: was Rawls’s revival of a contractualist approach to liberal legitimacy a fruitful move for liberalism and/or the social contract tradition? The last section contains a largely negative answer to that question. Nonetheless the chapter's conclusion shows that the research programme of political liberalism provided and continues to provide illuminating insights into the limitations of liberal contractualism, especially under conditions of persistent and radical diversity. The programme is, however, less receptive to challenges to do with the relative decline of the power of modern states

Constitutivism

A brief explanation and overview of constitutivism

Immunological corollary of the pulmonary mycobiome in bronchiectasis:The Cameb study

Understanding the composition and clinical importance of the fungal mycobiome was recently identified as a key topic in a “research priorities” consensus statement for bronchiectasis. Patients were recruited as part of the CAMEB study: an international multicentre cross-sectional Cohort of Asian and Matched European Bronchiectasis patients. The mycobiome was determined in 238 patients by targeted amplicon shotgun sequencing of the 18S–28S rRNA internally transcribed spacer regions ITS1 and ITS2. Specific quantitative PCR for detection of and conidial quantification for a range of airway Aspergillus species was performed. Sputum galactomannan, Aspergillus specific IgE, IgG and TARC (thymus and activation regulated chemokine) levels were measured systemically and associated to clinical outcomes. The bronchiectasis mycobiome is distinct and characterised by specific fungal genera, including Aspergillus, Cryptococcus and Clavispora. Aspergillus fumigatus (in Singapore/Kuala Lumpur) and Aspergillus terreus (in Dundee) dominated profiles, the latter associating with exacerbations. High frequencies of Aspergillus-associated disease including sensitisation and allergic bronchopulmonary aspergillosis were detected. Each revealed distinct mycobiome profiles, and associated with more severe disease, poorer pulmonary function and increased exacerbations. The pulmonary mycobiome is of clinical relevance in bronchiectasis. Screening for Aspergillus-associated disease should be considered even in apparently stable patients.MOE (Min. of Education, S’pore)NMRC (Natl Medical Research Council, S’pore)Published versio