Erdosteine in children and adults with bronchiectasis (BETTER trial): study protocol for a multicentre, double-blind, randomised controlled trial.

INTRODUCTION: Bronchiectasis is a worldwide chronic lung disorder where exacerbations are common. It affects people of all ages, but especially Indigenous populations in high-income nations. Despite being a major contributor to chronic lung disease, there are no licensed therapies for bronchiectasis and there remain relatively few randomised controlled trials (RCTs) conducted in children and adults. Our RCT will address some of these unmet needs by evaluating whether the novel mucoactive agent, erdosteine, has a therapeutic role in children and adults with bronchiectasis.Our primary aim is to determine in children and adults aged 2-49 years with bronchiectasis whether regular erdosteine over a 12-month period reduces acute respiratory exacerbations compared with placebo. Our primary hypothesis is that people with bronchiectasis who regularly use erdosteine will have fewer exacerbations than those receiving placebo.Our secondary aims are to determine the effect of the trial medications on quality of life (QoL) and other clinical outcomes (exacerbation duration, time-to-next exacerbation, hospitalisations, lung function, adverse events). We will also assess the cost-effectiveness of the intervention. METHODS AND ANALYSIS: We are undertaking an international multicentre, double-blind, placebo-RCT to evaluate whether 12 months of erdosteine is beneficial for children and adults with bronchiectasis. We will recruit 194 children and adults with bronchiectasis to a parallel, superiority RCT at eight sites across Australia, Malaysia and Philippines. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, exacerbation duration, time-to-next exacerbation, hospitalisations and lung function. ETHICS AND DISSEMINATION: The Human Research Ethics Committees (HREC) of Children's Health Queensland (for all Australian sites), University of Malaya Medical Centre (Malaysia) and St. Luke's Medical Centre (Philippines) approved the study. We will publish the results and share the outcomes with the academic and medical community, funding and relevant patient organisations. TRIAL REGISTRATION NUMBER: ACTRN12621000315819.

Extracellular traps are evident in Romanowsky-stained smears of bronchoalveolar lavage from children with non-cystic fibrosis bronchiectasis.

BACKGROUND AND OBJECTIVE: The importance of extracellular traps (ETs) in chronic respiratory conditions is increasingly recognized but their role in paediatric bronchiectasis is poorly understood. The specialized techniques currently required to study ETs preclude routine clinical use. A simple and cost-effective ETs detection method is needed to support diagnostic applications. We aimed to determine whether ETs could be detected using light microscopy-based assessment of Romanowsky-stained bronchoalveolar lavage (BAL) slides from children with bronchiectasis, and whether the ETs cellular origin could be determined. METHODS: Archived Romanowsky-stained BAL slides from a cross-sectional study of children with bronchiectasis were examined for ETs using light microscopy. The cellular origin of individual ETs was determined based on morphology and physical contact with surrounding cell(s). RESULTS: ETs were observed in 78.7% (70/89) of BAL slides with neutrophil (NETs), macrophage (METs), eosinophil (EETs) and lymphocyte (LETs) ETs observed in 32.6%, 51.7%, 4.5% and 9%, respectively. ETs of indeterminate cellular origin were present in 59.6% of slides. Identifiable and indeterminate ETs were co-detected in 43.8% of slides. CONCLUSION: BAL from children with bronchiectasis commonly contains multiple ET types that are detectable using Romanowsky-stained slides. While specialist techniques remain necessary to determining the cellular origin of all ETs, screening of Romanowsky-stained slides presents a cost-effective method that is well-suited to diagnostic settings. Our findings support further research to determine whether ETs can be used to define respiratory endotypes and to understand whether ETs-specific therapies may be required to resolve airway inflammation among children with bronchiectasis.

Prevalence and subtyping of biofilms present in bronchoalveolar lavage from children with protracted bacterial bronchitis or non-cystic fibrosis bronchiectasis: a cross-sectional study.

BACKGROUND: Lower airway biofilms are hypothesised to contribute to poor treatment outcomes among children with chronic lung disease; however, data are scarce. We aimed to determine the presence and prevalence of biofilm in bronchoalveolar lavage from children with protracted bacterial bronchitis (PBB) or bronchiectasis; whether biofilm was associated with signs of lower airway infection; and whether biofilms were consistent with an upper or lower airway origin. METHODS: In this cross-sectional study, fluorescent microscopy techniques were used to detect biofilm in archived bronchoalveolar lavage specimens from a paediatric cohort (age <18 years) with PBB or bronchiectasis who were prospectively recruited to observational studies of chronic cough at Royal Children's Hospital (Brisbane, Australia) or Royal Darwin Hospital (Darwin, Australia). Children with cystic fibrosis were excluded. Lower airway infection was defined as bronchoalveolar lavage neutrophil percentage of 15% or more, or a culture of a bacterial pathogen at 104 colony-forming units per mL or more, or both. Biofilms were subtyped as either of lower airway origin (unrelated to squamous epithelial cells) or of upper airway origin (observed in close association with squamous epithelial cells). Bronchoalveolar lavages were considered contaminated with upper airway secretions if the squamous cell proportion was more than ten cells per 1000 nucleated cells (>1%). Primary outcomes were the prevalence of each biofilm subtype among children with PBB compared with children with bronchiectasis. Secondary outcomes were the prevalence of each biofilm subtype among children with signs of lower airway infection compared to children without. FINDINGS: Biofilm testing was performed on 144 bronchoalveolar lavage specimens collected between Jan 1, 2011, and Dec 16, 2014, and preserved at -80°C before biofilm testing (69 children with PBB from Brisbane and 75 children with bronchiectasis from Darwin). The prevalence of lower airway biofilms (unrelated to squamous epithelial cells) was similar among the children with PBB (25 [36%] of 69) and children with bronchiectasis (31 [41%] of 75; odds ratio [OR] 1·24, 95% CI 0·63-2·43), but higher among children with signs of lower airway infection (46 [48%] of 95) than children without (eight [19%] of 43; OR 4·11, 95% CI 1·73-9·78), irrespective of the underlying diagnosis. By contrast, upper airway biofilms (associated with squamous epithelial cells) were more prevalent among children with bronchiectasis (32 [43%] of 75) than children with PBB (16 [23%] of 69; OR 2·47, 95% CI 1·20-5·08) and were unrelated to lower airway infection. Upper airway contamination was uncommon (eight [11%] of 71) and was not evident in 23 (79%) of 29 bronchoalveolar lavages that were positive for upper airway biofilms. INTERPRETATION: Lower airway biofilms are prevalent, but not ubiquitous, in bronchoalveolar lavage from children with PBB or bronchiectasis, suggesting anti-biofilm therapies might be beneficial for some children. Detection of upper airway biofilms in bronchoalveolar lavage that did not have signs of contamination suggests that microaspiration might be important in some children. Specimen quality measures are recommended for future studies to account for the presence of upper airway biofilms. FUNDING: Financial Markets for Children Project Grant, National Health and Medical Research Council of Australia, Rebecca L Cooper Medical Research Foundation, Queensland Children's Hospital Foundation, and BrightSpark Foundation.

Absence of human papillomavirus in nasopharyngeal swabs from infants in a population at high risk of human papillomavirus infection.

Maternal urogenital human papillomavirus (HPV) infection may place neonates at risk of HPV acquisition and subsequently lower respiratory infections as HPV can influence development of immunity. The respiratory HPV prevalence is not known in remote-dwelling Aboriginal infants, who are at high risk of respiratory infection and where the population prevalence of urogenital HPV in women is high. These data are necessary to inform HPV vaccination regimens. A retrospective analysis using PCR specific for HPV was performed on 64 stored nasopharyngeal swabs from remote-dwelling Aboriginal infants < 6 months of age, with and without hospitalised pneumonia. HPV DNA was not detected in any specimen. Despite the negative result, we cannot exclude a role for HPV in respiratory infections affecting infants in this population; however, our data do not support HPV as an important contributor to acute respiratory infection in remote-dwelling Aboriginal children.

Panel 4: Recent advances in understanding the natural history of the otitis media microbiome and its response to environmental pressures.

OBJECTIVE: To perform a comprehensive review of otitis media microbiome literature published between 1st July 2015 and 30th June 2019. DATA SOURCES: PubMed database, National Library of Medicine. REVIEW METHODS: Key topics were assigned to each panel member for detailed review. Draft reviews were collated and circulated for discussion when the panel met at the 20th International Symposium on Recent Advances in Otitis Media in June 2019. The final draft was prepared with input from all panel members. CONCLUSIONS: Much has been learned about the different types of bacteria (including commensals) present in the upper respiratory microbiome, but little is known about the virome and mycobiome. A small number of studies have investigated the middle ear microbiome; however, current data are often limited by small sample sizes and methodological heterogeneity between studies. Furthermore, limited reporting of sample collection methods mean that it is often difficult to determine whether bacteria detected in middle ear fluid specimens originated from the middle ear or the external auditory canal. Recent in vitro studies suggest that bacterial interactions in the nasal/nasopharyngeal microbiome may affect otitis media pathogenesis by modifying otopathogen behaviours. Impacts of environmental pressures (e.g. smoke, nutrition) and clinical interventions (e.g. vaccination, antibiotics) on the upper respiratory and middle ear microbiomes remain poorly understood as there are few data. IMPLICATIONS FOR PRACTICE: Advances in understanding bacterial dynamics in the upper airway microbiome are driving development of microbiota-modifying therapies to prevent or treat disease (e.g. probiotics). Further advances in otitis media microbiomics will likely require technological improvements that overcome the current limitations of OMICs technologies when applied to low volume and low biomass specimens that potentially contain high numbers of host cells. Improved laboratory models are needed to elucidate mechanistic interactions among the upper respiratory and middle ear microbiomes. Minimum reporting standards are critically needed to improve inter-study comparisons and enable future meta-analyses.

Human and Extracellular DNA Depletion for Metagenomic Analysis of Complex Clinical Infection Samples Yields Optimized Viable Microbiome Profiles.

Metagenomic sequencing is a promising approach for identifying and characterizing organisms and their functional characteristics in complex, polymicrobial infections, such as airway infections in people with cystic fibrosis. These analyses are often hampered, however, by overwhelming quantities of human DNA, yielding only a small proportion of microbial reads for analysis. In addition, many abundant microbes in respiratory samples can produce large quantities of extracellular bacterial DNA originating either from biofilms or dead cells. We describe a method for simultaneously depleting DNA from intact human cells and extracellular DNA (human and bacterial) in sputum, using selective lysis of eukaryotic cells and endonuclease digestion. We show that this method increases microbial sequencing depth and, consequently, both the number of taxa detected and coverage of individual genes such as those involved in antibiotic resistance. This finding underscores the substantial impact of DNA from sources other than live bacteria in microbiological analyses of complex, chronic infection specimens.

Multiple Respiratory Microbiota Profiles Are Associated With Lower Airway Inflammation in Children With Protracted Bacterial Bronchitis.

BACKGROUND: Effective management of protracted bacterial bronchitis (PBB) is needed to prevent chronic disease (eg, bronchiectasis). Understanding the contributions of ongoing airway infection and inflammation is important to achieving optimal PBB treatments. The aim of this study was to compare BAL microbiota, bacterial biomass, and inflammatory markers in children with PBB and age-matched control patients. METHODS: BAL was prospectively collected from 28 children with PBB (median age, 1.7 years; range, 0.6-7.4) and 8 control patients (median age, 1.9 years; range, 0.4-4.7). BAL microbiology was determined using culture, 16S ribosomal RNA gene sequencing and bacterial biomass quantification. BAL inflammatory cells, IL-8, and IL-1ß were used to assess lower airway inflammation. RESULTS: Bacterial biomass, neutrophil percentage, IL-8, and IL-1ß levels were significantly higher in children with PBB compared with control patients. BAL microbiota in children with PBB was significantly different to that of control patients (permutational multivariate analysis of variance P = .001) and clustered into four distinct profiles that were either dominated by a respiratory pathogen or contained a more diverse microbiota including Prevotella species. Alpha diversity was unrelated to bacterial biomass, culture of recognized respiratory pathogens, or inflammatory markers. CONCLUSIONS: Neutrophilic inflammation in children with PBB was associated with multiple BAL microbiota profiles. Significant associations between inflammatory markers and bacterial biomass, but not alpha diversity, suggest that inflammation in children with PBB is not driven by single pathogenic species. Understanding the role of the entire respiratory microbiota in PBB pathogenesis may be important to determining whether bacteria other than the recognized pathogens contribute to disease recurrence and progression to bronchiectasis.

Bacteria and viruses in the nasopharynx immediately prior to onset of acute lower respiratory infections in Indigenous Australian children.

Acute lower respiratory infection (ALRI) is a major cause of hospitalization for Indigenous children in remote regions of Australia. The associated microbiology remains unclear. Our aim was to determine whether the microbes present in the nasopharynx before an ALRI were associated with its onset. A retrospective case-control/crossover study among Indigenous children aged up to 2 years. ALRI cases identified by medical note review were eligible where nasopharyngeal swabs were available: (1) 0-21 days before ALRI onset (case); (2) 90-180 days before ALRI onset (same child controls); and (3) from time and age-matched children without ALRI (different child controls). PCR assays determined the presence and/or load of selected respiratory pathogens. Among 104 children (182 recorded ALRI episodes), 120 case-same child control and 170 case-different child control swab pairs were identified. Human adenoviruses (HAdV) were more prevalent in cases compared to same child controls (18 vs 7%; OR = 3.08, 95% CI 1.22-7.76, p = 0.017), but this association was not significant in cases versus different child controls (15 vs 10%; OR = 1.93, 95% CI 0.97-3.87 (p = 0.063). No other microbes were more prevalent in cases compared to controls. Streptococcus pneumoniae (74%), Haemophilus influenzae (75%) and Moraxella catarrhalis (88%) were commonly identified across all swabs. In a pediatric population with a high detection rate of nasopharyngeal microbes, HAdV was the only pathogen detected in the period before illness presentation that was significantly associated with ALRI onset. Detection of other potential ALRI pathogens was similar between cases and controls.

The microbiome of otitis media with effusion in Indigenous Australian children.

INTRODUCTION: Indigenous Australian children have a high prevalence of otitis media with effusion (OME) and associated conductive hearing loss. Only three microbiological studies of middle ear fluid (MEF) from Indigenous Australian children with OME have been reported. All of these were reliant on culture or species-specific PCR assays. The aim of this study was to characterise the middle ear fluid (MEF), adenoid and nasopharyngeal (NP) microbiomes of Indigenous Australian children, using culture-independent 16S rRNA gene sequencing. METHODS: MEF, NP swabs and adenoid specimens were collected from 11 children in the Alice Springs region of Central Australia. Bacterial communities in these specimens were characterised using 16S rRNA gene sequencing. RESULTS: The microbiota in MEF samples were dominated (>50% relative abundance) by operational taxonomic units (OTUs) consistent with Alloiococcus otitidis (6/11), Haemophilus influenzae (3/11) or Streptococcus sp. (specifically, Mitis group streptococci which includes Streptococcus pneumoniae) (1/11). Anatomical site selectivity was indicated by the presence of a single conserved Haemophilus OTU in 7/11 MEF samples. In comparison, there were ten distinct Haemophilus OTUs observed across the NP and adenoid samples. Despite significant differences between the MEF and NP/adenoid microbiomes, Streptococcus sp., H. influenzae and Moraxella catarrhalis OTUs were common to all sample types. Co-occurrence of classical otopathogens in paired MEF and NP/Adenoid samples is consistent with earlier culture-based studies. CONCLUSION: These data highlight the need to further assess H. influenzae traits important in otitis media and to understand the role of canal flora, especially A. otitidis, in populations with a high prevalence of tympanic membrane perforation.

Deriving accurate microbiota profiles from human samples with low bacterial content through post-sequencing processing of Illumina MiSeq data.

BACKGROUND: The rapid expansion of 16S rRNA gene sequencing in challenging clinical contexts has resulted in a growing body of literature of variable quality. To a large extent, this is due to a failure to address spurious signal that is characteristic of samples with low levels of bacteria and high levels of non-bacterial DNA. We have developed a workflow based on the paired-end read Illumina MiSeq-based approach, which enables significant improvement in data quality, post-sequencing. We demonstrate the efficacy of this methodology through its application to paediatric upper-respiratory samples from several anatomical sites. RESULTS: A workflow for processing sequence data was developed based on commonly available tools. Data generated from different sample types showed a marked variation in levels of non-bacterial signal and 'contaminant' bacterial reads. Significant differences in the ability of reference databases to accurately assign identity to operational taxonomic units (OTU) were observed. Three OTU-picking strategies were trialled as follows: de novo, open-reference and closed-reference, with open-reference performing substantially better. Relative abundance of OTUs identified as potential reagent contamination showed a strong inverse correlation with amplicon concentration allowing their objective removal. The removal of the spurious signal showed the greatest improvement in sample types typically containing low levels of bacteria and high levels of human DNA. A substantial impact of pre-filtering data and spurious signal removal was demonstrated by principal coordinate and co-occurrence analysis. For example, analysis of taxon co-occurrence in adenoid swab and middle ear fluid samples indicated that failure to remove the spurious signal resulted in the inclusion of six out of eleven bacterial genera that accounted for 80% of similarity between the sample types. CONCLUSIONS: The application of the presented workflow to a set of challenging clinical samples demonstrates its utility in removing the spurious signal from the dataset, allowing clinical insight to be derived from what would otherwise be highly misleading output. While other approaches could potentially achieve similar improvements, the methodology employed here represents an accessible means to exclude the signal from contamination and other artefacts.

Emerging drugs for bronchiectasis: an update.

INTRODUCTION: Recent research has confirmed the increasing burden of bronchiectasis, in affluent and developing countries. Bronchiectasis, the destruction and dilation of airways, is due to a variety of causes and is characterised by a self-perpetuating cycle of airway inflammation, infection and obstruction that results in substantial morbidity and mortality. Improved therapies that address these three components, and the diseases that both cause and result from bronchiectasis are required. AREAS COVERED: In this review, we update our previous summary of the clinical features, pathophysiology and epidemiology of bronchiectasis among adults and children, highlighting the most recent advances in therapeutics. We discuss current treatment strategies and then identify key goals for future research on the causes and treatments of a variety of types of bronchiectasis. EXPERT OPINION: Bronchiectasis remains an orphan disease with respect to the development of new therapies. There has been progress in the recognition and studies but further research is now required on the pathogenesis, prevention, and treatment of bronchiectasis in order to decrease its high burden. Such advances will require a concerted, global effort to coordinate studies of both the pathophysiology and potential treatments of this heterogeneous, chronic disease that affects people of all ages and demographics.

Detection of biofilm in bronchoalveolar lavage from children with non-cystic fibrosis bronchiectasis.

BACKGROUND: The presence of Pseudomonas aeruginosa biofilms in lower airway specimens from cystic fibrosis (CF) patients is well established. To date, biofilm has not been demonstrated in bronchoalveolar lavage (BAL) from people with non-CF bronchiectasis. The aim of this study was to determine (i) if biofilm was present in BAL from children with and without bronchiectasis, and (ii) if biofilm detection differed between sequentially collected BAL. METHODS: Testing for biofilm in two sequentially collected BAL from children with and without bronchiectasis was done using BacLight™ live-dead staining and lectin staining for extracellular polymeric biofilm matrices. Bacterial culture and cytological measures were performed on the first and second lavages, respectively. Clinically important BAL infection was defined as >104 cfu of respiratory pathogens/ml BAL. RESULTS: Biofilm was detected in BAL from seven of eight (87.5%) children with bronchiectasis (aged 0.8-6.9 years), but was not detected in any of three controls (aged 1.3-8.6 years). The biofilms contained both live and dead bacteria irrespective of antibiotic use prior to bronchoscopy. Biofilm was detected more frequently in the second lavage than the first. Three of the seven biofilm-positive BAL were culture-positive for respiratory pathogens at clinically important levels. CONCLUSIONS: Biofilm is present in BAL from children with non-CF bronchiectasis even when BAL-defined clinically important infection was absent. Studies to characterize lower airway biofilms and determine how biofilm contributes to bronchiectasis disease progression and treatment outcomes are necessary. Pediatr Pulmonol. 2015; 50:284-292. © 2014 Wiley Periodicals, Inc.

Directly sampling the lung of a young child with cystic fibrosis reveals diverse microbiota.

RATIONALE: The airways of people with cystic fibrosis (CF) are chronically infected with a variety of bacterial species. Although routine culture methods are usually used to diagnose these infections, culture-independent, DNA-based methods have identified many bacterial species in CF respiratory secretions that are not routinely cultured. Many prior culture-independent studies focused either on microbiota in explanted CF lungs, reflecting end-stage disease, or those in oropharyngeal swabs, which likely sample areas in addition to the lower airways. Therefore, it was unknown whether the lower airways of children with CF, well before end-stage but with symptomatic lung disease, truly contained diverse microbiota. OBJECTIVES: To define the microbiota in the diseased lung tissue of a child who underwent lobectomy for severe, localized CF lung disease. METHODS: After pathologic examination verified that this child's lung tissue reflected CF lung disease, we used bacterial ribosomal RNA gene pyrosequencing and computational phylogenetic analysis to identify the microbiota in serial sections of the tissue. MEASUREMENTS AND MAIN RESULTS: This analysis identified diverse, and anatomically heterogeneous, bacterial populations in the lung tissue that contained both culturable and nonculturable species, including abundant Haemophilus, Ralstonia, and Propionibacterium species. Routine clinical cultures identified only Staphylococcus aureus, which represented only a small fraction of the microbiota found by sequencing. Microbiota analysis of an intraoperative oropharyngeal swab identified predominantly Streptococcus species. The oropharyngeal findings therefore represented the lung tissue microbiota poorly, in agreement with findings from earlier studies of oropharyngeal swabs in end-stage disease. CONCLUSIONS: These results support the concept that diverse and spatially heterogeneous microbiota, not necessarily dominated by "traditional CF pathogens," are present in the airways of young, symptomatic children with early CF lung disease.

Three clinically distinct chronic pediatric airway infections share a common core microbiota.

RATIONALE: DNA-based microbiological studies are moving beyond studying healthy human microbiota to investigate diverse infectious diseases, including chronic respiratory infections, such as those in the airways of people with cystic fibrosis (CF) and non-CF bronchiectasis. The species identified in the respiratory secretion microbiota from such patients can be classified into those that are common and abundant among similar subjects (core) versus those that are infrequent and rare (satellite). This categorization provides a vital foundation for investigating disease pathogenesis and improving therapy. However, whether the core microbiota of people with different respiratory diseases, which are traditionally associated with specific culturable pathogens, are unique or shared with other chronic infections of the lower airways is not well studied. Little is also known about how these chronic infection microbiota change from childhood to adulthood. OBJECTIVES: We sought to compare the core microbiota in respiratory specimens from children and adults with different chronic lung infections. METHODS: We used bacterial 16S rRNA gene pyrosequencing, phylogenetic analysis, and ecological statistical tools to compare the core microbiota in respiratory samples from three cohorts of symptomatic children with clinically distinct airway diseases (protracted bacterial bronchitis, bronchiectasis, CF), and from four healthy children. We then compared the core pediatric respiratory microbiota with those in samples from adults with bronchiectasis and CF. MEASUREMENTS AND MAIN RESULTS: All three pediatric disease cohorts shared strikingly similar core respiratory microbiota that differed from adult CF and bronchiectasis microbiota. The most common species in pediatric disease cohort samples were also detected in those from healthy children. The adult CF and bronchiectasis microbiota also differed from each other, suggesting common early infection airway microbiota that diverge by adulthood. The shared core pediatric microbiota included both traditional pathogens and many species not routinely identified by standard culture. CONCLUSIONS: Our results indicate that these clinically distinct chronic airway infections share common early core microbiota, which are likely shaped by natural aspiration and impaired clearance of the same airway microbes, but that disease-specific characteristics select for divergent microbiota by adulthood. Longitudinal and interventional studies will be required to define the relationships between microbiota, treatments, and disease progression.

Quantitative PCR confirms culture as the gold standard for detection of lower airway infection by nontypeable Haemophilus influenzae in Australian Indigenous children with bronchiectasis.

Correlation was observed between quantitative PCR and semi-quantitative culture for definition of Haemophilus influenzae infection in bronchoalveolar lavage specimens from 81 children with bronchiectasis. However, qPCR data correlated less well with airway neutrophilia, and supports continued use of culture as the gold standard for defining H. influenzae lower airway infection.

Emerging drugs for bronchiectasis.

INTRODUCTION: The global burden of disease due to bronchiectasis is high, disproportionately impacting developing countries and disadvantaged populations. Bronchiectasis, the destruction and dilation of airways, is due to a variety of causes and is characterized by a self-perpetuating cycle of airway inflammation, infection and obstruction that results in substantial morbidity and mortality. Although many therapies have been tested that address each of these three components, as well as the diseases that both cause and result from bronchiectasis, there have been few randomized, placebo-controlled trials. AREAS COVERED: In this review, current knowledge of the clinical features, pathophysiology and epidemiology of bronchiectasis among both adults and children is summarized. We discuss the quality and extent of evidence supporting current treatment strategies, focusing on therapies for which the strongest evidence of efficacy exists. We then identify key goals for future research on the causes and treatments of a variety of types of bronchiectasis. EXPERT OPINION: Significant advances in the prevention and treatment of bronchiectasis will require substantially improved understanding of the pathogenesis of this orphan disease. A concerted, global effort to coordinate studies of both the pathophysiology and potential treatments of bronchiectasis, in its many forms, could lead to substantial improvements in outcomes.