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Bronchiectasis is characterised by pathological dilation of the airways. More specifically, the radiographic demonstration of airway enlargement is the common feature of a heterogeneous set of conditions and clinical presentations. No approved therapies exist for the condition other than for bronchiectasis caused by cystic fibrosis. The heterogeneity of bronchiectasis is a major challenge in clinical practice and the main reason for difficulty in achieving endpoints in clinical trials. Recent observations of the past 2 years have improved the understanding of physicians regarding bronchiectasis, and have indicated that it might be more effective to classify patients in a different way. Patients could be categorised according to a heterogeneous group of endotypes (defined by a distinct functional or pathobiological mechanism) or by clinical phenotypes (defined by relevant and common features of the disease). In doing so, more specific therapies needed to effectively treat patients might finally be developed. Here, we describe some of the recent advances in endotyping, genetics, and disease heterogeneity of bronchiectasis including observations related to the microbiome.

Cystic fibrosis is a common life-limiting autosomal recessive genetic disorder, with highest prevalence in Europe, North America, and Australia. The disease is caused by mutation of a gene that encodes a chloride-conducting transmembrane channel called the cystic fibrosis transmembrane conductance regulator (CFTR), which regulates anion transport and mucociliary clearance in the airways. Functional failure of CFTR results in mucus retention and chronic infection and subsequently in local airway inflammation that is harmful to the lungs. CFTR dysfunction mainly affects epithelial cells, although there is evidence of a role in immune cells. Cystic fibrosis affects several body systems, and morbidity and mortality is mostly caused by bronchiectasis, small airways obstruction, and progressive respiratory impairment. Important comorbidities caused by epithelial cell dysfunction occur in the pancreas (malabsorption), liver (biliary cirrhosis), sweat glands (heat shock), and vas deferens (infertility). The development and delivery of drugs that improve the clearance of mucus from the lungs and treat the consequent infection, in combination with correction of pancreatic insufficiency and undernutrition by multidisciplinary teams, have resulted in remarkable improvements in quality of life and clinical outcomes in patients with cystic fibrosis, with median life expectancy now older than 40 years. Innovative and transformational therapies that target the basic defect in cystic fibrosis have recently been developed and are effective in improving lung function and reducing pulmonary exacerbations. Further small molecule and gene-based therapies are being developed to restore CFTR function; these therapies promise to be disease modifying and to improve the lives of people with cystic fibrosis.

Substantial population morbidity is likely

Testing for underlying etiology is a key part of bronchiectasis management, but it is unclear whether the same extent of testing is required across the spectrum of disease severity. The aim of the present study was to identify the etiology of bronchiectasis across European cohorts and according to different levels of disease severity. We conducted an analysis of seven databases of adult outpatients with bronchiectasis prospectively enrolled at the bronchiectasis clinics of university teaching hospitals in Monza, Italy; Dundee and Newcastle, United Kingdom; Leuven, Belgium; Barcelona, Spain; Athens, Greece; and Galway, Ireland. All the patients at every site underwent the same comprehensive diagnostic workup as suggested by the British Thoracic Society. Among the 1,258 patients enrolled, an etiology of bronchiectasis was determined in 60%, including postinfective (20%), chronic obstructive pulmonary disease related (15%), connective tissue disease related (10%), immunodeficiency related (5.8%), and asthma related (3.3%). An etiology leading to a change in patient's management was identified in 13% of the cases. No significant differences in the etiology of bronchiectasis were present across different levels of disease severity, with the exception of a higher prevalence of chronic obstructive pulmonary disease-related bronchiectasis (P < 0.001) and a lower prevalence of idiopathic bronchiectasis (P = 0.029) in patients with severe disease. Physicians should not be guided by disease severity in suspecting specific etiologies in patients with bronchiectasis, although idiopathic bronchiectasis appears to be less common in patients with the most severe disease.

Bronchiectasis is a disease associated with chronic progressive and irreversible dilatation of the bronchi and is characterised by chronic infection and associated inflammation. The prevalence of bronchiectasis is age-related and there is some geographical variation in incidence, prevalence and clinical features. Most bronchiectasis is reported to be idiopathic however post-infectious aetiologies dominate across Asia especially secondary to tuberculosis. Most focus to date has been on the study of airway bacteria, both as colonisers and causes of exacerbations. Modern molecular technologies including next generation sequencing (NGS) have become invaluable tools to identify microorganisms directly from sputum and which are difficult to culture using traditional agar based methods. These have provided important insight into our understanding of emerging pathogens in the airways of people with bronchiectasis and the geographical differences that occur. The contribution of the lung microbiome, its ethnic variation, and subsequent roles in disease progression and response to therapy across geographic regions warrant further investigation. This review summarises the known geographical differences in the aetiology, epidemiology and microbiology of bronchiectasis. Further, we highlight the opportunities offered by emerging molecular technologies such as -omics to further dissect out important ethnic differences in the prognosis and management of bronchiectasis.

The diagnosis, investigation and particularly management of bronchiectasis has been largely empirical and the subject of relatively few controlled clinical trials. There are no clear guidelines, although an Australian position statement has been published concerning bronchiectasis in children. The purposes of these guidelines were therefore threefold: (1) to identify relevant studies in non-cystic fibrosis (CF) bronchiectasis; (2) to provide guidelines on management based on published studies where possible or a consensus view; and (3) to identify gaps in our knowledge and identify areas for future study.

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.

The prevalence of bronchiectasis is high in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and it has been associated with exacerbations and bacterial colonization. These have demonstrated some degree of prognostic value in patients with COPD but no information about the relationship between bronchiectasis and mortality in patients with COPD is currently available. To assess the prognostic value of bronchiectasis in patients with moderate-to-severe COPD. Multicenter prospective observational study in consecutive patients with moderate-to-severe COPD. Bronchiectasis was diagnosed by high-resolution computed tomography scan. A complete standardized protocol was used in all patients covering general, anthrophometric, functional, clinical, and microbiologic data. After follow-up, the vital status was recorded in all patients. Multivariate Cox analysis was used to determine the independent adjusted prognostic value of bronchiectasis. Ninety-nine patients in Global Initiative for Chronic Obstructive Lung Disease (GOLD) II, 85 in GOLD III, and 17 in GOLD IV stages were included. Bronchiectasis was present in 115 (57.2%) patients. During the follow-up (median, 48 mo [interquartile range, 35-53]) there were 51 deaths (43 deaths in the bronchiectasic group). Bronchiectasis was associated with an increased risk of fully adjusted mortality (hazard ratio, 2.54; 95% confidence interval, 1.16-5.56; P = 0.02). Bronchiectasis was associated with an independent increased risk of all-cause mortality in patients with moderate-to-severe COPD.

Bronchiectasis causes substantial morbidity in patients with cystic fibrosis. In this study, children were followed from diagnosis until 3 years of age. Neutrophil elastase activity in the lung at 3 months of age was associated with persistent bronchiectasis. Illness and death from cystic fibrosis are due primarily to progressively destructive lung disease resulting in bronchiectasis and respiratory failure. Computed tomography (CT) can detect changes in the lungs associated with bronchiectasis 1 , 2 and evidence of structural lung disease in children with cystic fibrosis as young as 10 weeks of age. 3 – 8 The true prevalence of bronchiectasis among children with cystic fibrosis is unknown; however, studies conducted by the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) and the Australasian Cystic Fibrosis Bronchoalveolar Lavage study group have shown that 50 to 70% of patients have CT-defined bronchiectasis by . . .

Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory properties. We tested the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and improve health-related quality of life in patients with non-cystic fibrosis bronchiectasis. We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand. Between Feb 12, 2008, and Oct 15, 2009, we enrolled patients who were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defined by high-resolution CT scan. We randomly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio, with a permuted block size of six and sequential assignment stratified by centre. Participants, research assistants, and investigators were masked to treatment allocation. The coprimary endpoints were rate of event-based exacerbations in the 6-month treatment period, change in forced expiratory volume in 1 s (FEV1) before bronchodilation, and change in total score on St George's respiratory questionnaire (SGRQ). Analyses were by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493. 71 patients were in the azithromycin group and 70 in the placebo group. The rate of event-based exacerbations was 0·59 per patient in the azithromycin group and 1·57 per patient in the placebo group in the 6-month treatment period (rate ratio 0·38, 95% CI 0·26–0·54; p<0·0001). Prebronchodilator FEV1 did not change from baseline in the azithromycin group and decreased by 0·04 L in the placebo group, but the difference was not significant (0·04 L, 95% CI −0·03 to 0·12; p=0·251). Additionally, change in SGRQ total score did not differ between the azithromycin (–5·17 units) and placebo groups (–1·92 units; difference −3·25, 95% CI −7·21 to 0·72; p=0·108). Azithromycin is a new option for prevention of exacerbations in patients with non-cystic fibrosis bronchiectasis with a history of at least one exacerbation in the past year. Health Research Council of New Zealand and Auckland District Health Board Charitable Trust.