Experiences of children with bronchiectasis and their parents in a novel play-based therapeutic exercise programme: a qualitative analysis.

OBJECTIVES: To explore the experiences and perceptions of children with bronchiectasis and their parents regarding an 8-week play-based therapeutic exercise programme. DESIGN: Qualitative study with inductive content analysis. SETTING: Individual semistructured interviews were conducted. Interview recordings were transcribed verbatim, and coding was guided by the content. Content categories were established via consensus moderation. PARTICIPANTS: 10 parents and 10 children with bronchiectasis aged 5-12 years. RESULTS: From the perspective of children, the most important components of the programme were fun with friends and being active at home as a family. Parents valued the community-based sessions, perceived the programme to be engaging and motivating. Parents perceived improvements in their child's endurance, coordination and physical activity level. They described the home programme as fun but noted that finding time was difficult. Both parents and children thought that in-person exercise sessions would be better than exercise sessions delivered online. CONCLUSIONS: Children who participated in the play-based exercise programme, found it fun, motivating and accessible. Parents perceived positive impacts on fitness, coordination and physical activity. TRIAL REGISTRATION NUMBER: The trial was registered with, Australian and New Zealand Clinical Trials Register (ACTRN12619001008112).

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.

Improving the Diagnosis and Treatment of Paediatric Bronchiectasis Through Research and Translation.

Bronchiectasis, particularly in children, is an increasingly recognised yet neglected chronic lung disorder affecting individuals in both low-to-middle and high-income countries. It has a high disease burden and there is substantial inequity within and between settings. Furthermore, compared with other chronic lung diseases, considerably fewer resources are available for children with bronchiectasis. The need to prevent bronchiectasis and to reduce its burden also synchronously aligns with its high prevalence and economic costs to health services and society. Like many chronic lung diseases, bronchiectasis often originates early in childhood, highlighting the importance of reducing the disease burden in children. Concerted efforts are therefore needed to improve disease detection, clinical management and equity of care. Modifiable factors in the causal pathways of bronchiectasis, such as preventing severe and recurrent lower respiratory infections should be addressed, whilst also acknowledging the role played by social determinants of health. Here, we highlight the importance of early recognition/detection and optimal management of bronchiectasis in children, and outline our research, which is attempting to address important clinical knowledge gaps discussed in a recent workshop. The research is grouped under three themes focussing upon primary prevention, improving diagnosis and disease characterisation, and providing better management. Our hope is that others in multiple settings will undertake additional studies in this neglected field to further improve the lives of people with bronchiectasis. We also provide a resource list with links to help inform consumers and healthcare professionals about bronchiectasis and its recognition and management.

Bronchiectasis among Indigenous adults in the Top End of the Northern Territory, 2011-2020: a retrospective cohort study.

OBJECTIVES: To assess the prevalence of bronchiectasis among Aboriginal and Torres Strait Islander (Indigenous) adults in the Top End of the Northern Territory, and mortality among Indigenous adults with bronchiectasis. STUDY DESIGN: Retrospective cohort study. SETTING, PARTICIPANTS: Aboriginal and Torres Strait Islander adults (18 years or older) living in the Top End Health Service region of the NT in whom bronchiectasis was confirmed by chest computed tomography (CT) during 1 January 2011 - 31 December 2020. MAIN OUTCOME MEASURES: Prevalence of bronchiectasis, and all-cause mortality among Indigenous adults with CT-confirmed bronchiectasis - overall, by sex, and by health district - based on 2011 population numbers (census data). RESULTS: A total of 23 722 Indigenous adults lived in the Top End Health Service region in 2011; during 2011-2020, 459 people received chest CT-confirmed diagnoses of bronchiectasis. Their median age was 47.5 years (interquartile range [IQR], 39.9-56.8 years), 254 were women (55.3%), and 425 lived in areas classified as remote (93.0%). The estimated prevalence of bronchiectasis was 19.4 per 1000 residents (20.6 per 1000 women; 18.0 per 1000 men). The age-adjusted prevalence of bronchiectasis was 5.0 (95% CI, 1.4-8.5) cases per 1000 people in the Darwin Urban health area, and 18-36 cases per 1000 people in the three non-urban health areas. By 30 April 2023, 195 people with bronchiectasis had died (42.5%), at a median age of 60.3 years (IQR, 50.3-68.9 years). CONCLUSION: The prevalence of bronchiectasis burden among Indigenous adults in the Top End of the NT is high, but differed by health district, as is all-cause mortality among adults with bronchiectasis. The socio-demographic and other factors that contribute to the high prevalence of bronchiectasis among Indigenous Australians should be investigated so that interventions for reducing its burden can be developed.

Change in health outcomes for First Nations children with chronic wet cough: rationale and study protocol for a multi-centre implementation science study.

BACKGROUND: In children, chronic wet cough may be a sign of underlying lung disease, including protracted bacterial bronchitis (PBB) and bronchiectasis. Chronic (> 4 weeks in duration) wet cough (without indicators pointing to alternative causes) that responds to antibiotic treatment is diagnostic of PBB. Timely recognition and management of PBB can prevent disease progression to irreversible bronchiectasis with lifelong consequences. However, detection and management require timely health-seeking by carers and effective management by clinicians. We aim to improve (a) carer health-seeking for chronic wet cough in their child and (b) management of chronic wet cough in children by clinicians. We hypothesise that implementing a culturally integrated program, which is informed by barriers and facilitators identified by carers and health practitioners, will result in improved lung health of First Nations children, and in the future, a reduced the burden of bronchiectasis through the prevention of the progression of protracted bacterial bronchitis to bronchiectasis. METHODS: This study is a multi-centre, pseudorandomised, stepped wedge design. The intervention is the implementation of a program. The program has two components: a knowledge dissemination component and an implementation component. The implementation is adapted to each study site using a combined Aboriginal Participatory Action Research and an Implementation Science approach, guided by the Consolidated Framework of Implementation Research. There are three categories of outcome measures related to (i) health (ii) cost, and (iii) implementation. We will measure health-seeking as the proportion of parents seeking help for their child in a 6-month period before the intervention and the same 6-month period (i.e., the same six calendar months) thereafter. The parent-proxy, Cough-specific Quality of Life (PC-QoL) will be the primary health-related outcome measure. DISCUSSION: We hypothesise that a tailored intervention at each site will result in improved health-seeking for carers of children with a chronic wet cough and improved clinician management of chronic wet cough. In addition, we expect this will result in improved lung health outcomes for children with a chronic wet cough. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry; ACTRN12622000430730 , registered 16 March 2022, Retrospectively registered.

Reducing exacerbations in children and adults with primary ciliary dyskinesia using erdosteine and/or azithromycin therapy (REPEAT trial): study protocol for a multicentre, double-blind, double-dummy, 2×2 partial factorial, randomised controlled trial.

INTRODUCTION: Primary ciliary dyskinesia (PCD) is a rare, progressive, inherited ciliopathic disorder, which is incurable and frequently complicated by the development of bronchiectasis. There are few randomised controlled trials (RCTs) involving children and adults with PCD and thus evidence of efficacy for interventions are usually extrapolated from people with cystic fibrosis. Our planned RCT seeks to address some of these unmet needs by employing a currently prescribed (but unapproved for long-term use in PCD) macrolide antibiotic (azithromycin) and a novel mucolytic agent (erdosteine). The primary aim of our RCT is to determine whether regular oral azithromycin and erdosteine over a 12-month period reduces acute respiratory exacerbations among children and adults with PCD. Our primary hypothesis is that: people with PCD who regularly use oral azithromycin and/or erdosteine will have fewer exacerbations than those receiving the corresponding placebo medications. Our secondary aims are to determine the effect of the trial medications on PCD-specific quality-of-life (QoL) and other clinical outcomes (lung function, time-to-next exacerbation, hospitalisations) and nasopharyngeal bacterial carriage and antimicrobial resistance. METHODS AND ANALYSIS: We are currently undertaking a multicentre, double-blind, double-dummy RCT to evaluate whether 12 months of azithromycin and/or erdosteine is beneficial for children and adults with PCD. We plan to recruit 104 children and adults with PCD to a parallel, 2×2 partial factorial superiority RCT at five sites across Australia. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, lung function and nasopharyngeal carriage by respiratory bacterial pathogens and their associated azithromycin resistance. ETHICS AND DISSEMINATION: Our RCT is conducted in accordance with Good Clinical Practice and the Australian legislation and National Health and Medical Research Council guidelines for ethical conduct of Research, including that for First Nations Australians. TRIAL REGISTRATION NUMBER: ACTRN12619000564156.

Bronchiectasis - Exercise as Therapy (BREATH): rationale and study protocol for a multi-center randomized controlled trial.

BACKGROUND: Globally, bronchiectasis (BE) unrelated to cystic fibrosis (CF) is recognized as a major cause of respiratory morbidity, mortality, and healthcare utilization. Children with BE regularly experience exacerbations of their condition resulting in frequent hospitalizations and decreased health-related quality of life (HR-QoL). Guidelines for the treatment and management of BE call for regular exercise as a means of improving aerobic fitness and HR-QoL. Moreover, research in adults with BE has shown that exercise can reduce the frequency of exacerbations, a potent predictor of future lung function decline and respiratory morbidity. Yet, to date, the health benefits resulting from therapeutic exercise have not been investigated in children with BE. The BREATH, Bronchiectasis - Exercise as Therapy, trial will test the efficacy of a novel 8-week, play-based therapeutic exercise program to reduce the frequency of acute exacerbations over 12 months in children with BE (aged ≥ 4 and < 13 years). Secondary aims are to determine the cost-effectiveness of the intervention and assess the program's impact on aerobic fitness, fundamental movement skill (FMS) proficiency, habitual physical activity, HR-QoL, and lung function. METHODS: This multi-center, observer-blinded, parallel-group (1:1 allocation), randomized controlled trial (RCT) will be conducted at three sites. One hundred and seventy-four children ≥ 4 and < 13 years of age with BE will be randomized to a developmentally appropriate, play-based therapeutic exercise program (eight, 60-min weekly sessions, supplemented by a home-based program) or usual care. After completing the baseline assessments, the number of exacerbations and secondary outcomes will be assessed immediately post-intervention, after 6 months of follow-up, and after 12 months of follow-up. Monthly, parental contact and medical review will document acute respiratory exacerbations and parameters for cost-effectiveness outcomes. DISCUSSION: The BREATH trial is the first fully powered RCT to test the effects of a therapeutic exercise on exacerbation frequency, fitness, movement competence, and HR-QoL in children with bronchiectasis. By implementing a developmentally appropriate, play-based exercise program tailored to the individual needs of children with bronchiectasis, the results have the potential for a major paradigm shift in the way in which therapeutic exercise is prescribed and implemented in children with chronic respiratory conditions. The exercise program can be readily translated. It does not require expensive equipment and can be delivered in a variety of settings, including the participant's home. The program has strong potential for translation to other pediatric patient groups with similar needs for exercise therapy, including those with obesity, childhood cancers, and neurological conditions such as cerebral palsy. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register (ANZCTR) ACTRN12619001008112.

Utility of a personalised Bronchiectasis Action Management Plan (BAMP) for children with bronchiectasis: protocol for a multicentre, double-blind parallel, superiority randomised controlled trial.

INTRODUCTION: Bronchiectasis is no longer considered rare or irreversible in children, yet it remains relatively under-researched and neglected in respiratory health globally. Bronchiectasis (including chronic suppurative lung disease) causes substantial morbidity for patients and significant impact on caregivers, especially during acute respiratory exacerbations. In other chronic respiratory diseases (eg, asthma), empowering consumers with an individualised plan for management of acute exacerbations improves clinical outcomes. However, in the absence of any such data specific to bronchiectasis, action management plans are rarely currently used in children or adults with bronchiectasis. We hypothesise that providing an individualised bronchiectasis action management plan (BAMP) to children with bronchiectasis reduces non-scheduled doctor consultations, compared with not having a BAMP. METHODS AND ANALYSIS: This multicentre, parallel, double-blind, randomised trial involving three urban Australian hospitals commenced in June 2018 and will include 198 children, aged <19 years with bronchiectasis who had 2 or more exacerbations in the previous 18 months. Children will be randomised to having an individualised BAMP or standard care (a decoy clinic letter). Primary caregivers will then be followed up monthly for 12 months. The primary outcome is the rate of acute non-scheduled doctor visits for respiratory exacerbations by 12 months. The main secondary outcomes are cough-specific quality of life scores at 6 and 12 months, overall exacerbation rate over 12 months, and proportion of children who received timely influenza vaccination by 30 May annually. ETHICS AND DISSEMINATION: The Human Research Ethics Committees of the Northern Territory Department of Health and Menzies School of Heath Research and Queensland Children's Hospital approved the study. The results of the trial will be submitted for publication and the BAMP made available free online. TRIAL REGISTRATION NUMBER: Australia and New Zealand Clinical Trials Register ACTRN12618000604202.

Factors associated with "Frequent Exacerbator" phenotype in children with bronchiectasis: The first report on children from the Australian Bronchiectasis Registry.

INTRODUCTION: In adults with bronchiectasis, multicentre data advanced the field including disease characterisation and derivation of phenotypes such as 'frequent exacerbator (FE)' (≥3 exacerbations/year). However, paediatric cohorts are largely limited to single centres and no scientifically derived phenotypes of paediatric bronchiectasis yet exists. Using paediatric data from the Australian Bronchiectasis Registry (ABR), we aimed to: (a) describe the clinical characteristics and compare Indigenous with non-Indigenous children, and (b) determine if a FE phenotype can be identified and if so, its associated factors. METHODS: We retrieved data of children (aged <18-years) with radiologically confirmed bronchiectasis, enrolled between March 2016-March 2020. RESULTS: Across five sites, 540 children [288 Indigenous; median age = 8-years (IQR 6-11)] were included. Baseline characteristics revealed past infection/idiopathic was the commonest (70%) underlying aetiology, most had cylindrical bronchiectasis and normal spirometry. Indigenous children (vs. non-Indigenous) had significantly more environmental tobacco smoke exposure (84% vs 32%, p < 0.0001) and lower birth weight (2797 g vs 3260 g, p < 0.0001). FE phenotype present in 162 (30%) children, was associated with being younger (ORadjusted = 0.85, 95%CI 0.81-0.90), more recent diagnosis of bronchiectasis (ORadjusted = 0.67; 95%CI 0.60-0.75), recent hospitalization (ORadj = 4.51; 95%CI 2.45-8.54) and Pseudomonas aeruginosa (PsA) infection (ORadjusted = 2.43; 95%CI 1.01-5.78). The FE phenotype were less likely to be Indigenous (ORadjusted = 0.14; 95%CI 0.03-0.65). CONCLUSION: Even within a single country, the characteristics of children with bronchiectasis differ among cohorts. A paediatric FE phenotype exists and is characterised by being younger with a more recent diagnosis, PsA infection and previous hospitalization. Prospective data to consolidate our findings characterising childhood bronchiectasis phenotypes are required.

Comparison of Profiles of First Nations and Non-First Nations Children With Bronchiectasis Over Two 5-Year Periods in the Northern Territory, Australia.

BACKGROUND: Although the burden of bronchiectasis is recognized globally, pediatric data are limited, particularly on trends over the years. Also, no published data exists regarding whether vitamin D deficiency or insufficiency and human T-cell lymphotropic virus type 1 (HTLV-1) infection, both found to be related to severe bronchiectasis in First Nations adults, also are important in children with bronchiectasis. RESEARCH QUESTION: Among children with bronchiectasis, (1) have the clinical and BAL profiles changed between two 5-year periods (period 1, 2007-2011; period 2, 2012-2016) and (b) are vitamin D deficiency or insufficiency, HTLV-1 infection, or both associated with radiologic severity of bronchiectasis? STUDY DESIGN AND METHODS: We analyzed the data from children with bronchiectasis prospectively enrolled at Royal Darwin Hospital, Australia, at the first diagnosis; that is, no child was included in both periods. Data collected include demographics, BAL, routine investigation bloods, and high-resolution CT scan of the chest evaluated using the Bhalla and modified Bhalla scores. RESULTS: The median age of the 299 children was 2.2 years (interquartile range, 1.5-3.7 years). One hundred sixty-eight (56%) were male and most were First Nations (92%). Overall, bronchiectasis was high over time, particularly among First Nations children. In the later period, numbers of non-First Nations children more than tripled, but did not reach statistical significance. In period 2 compared with period 1, fewer First Nations children demonstrated chronic cough (period 1, 61%; period 2, 47%; P = .03), and were younger, First Nations children were less likely to have received azithromycin (period 1, 42%; period 2, 21%; P < .001), and the BAL fluid of First Nations children showed lower Haemophilus influenzae and Moraxella catarrhalis infection. HTLV-1 infection was not detected, and vitamin D deficiency or insufficiency did not correlate with severity of bronchiectasis. INTERPRETATION: Bronchiectasis remains high particularly among First Nations children. Important changes in their profiles that arguably reflect improvements were present, but overall, the profiles remained similar. Although vitamin D deficiency was uncommon, its role in children with bronchiectasis requires further evaluation. HTLV-1 infection was nonexistent and is unlikely to play any role in First Nations children with bronchiectasis.

European Respiratory Society guidelines for the management of children and adolescents with bronchiectasis.

There is increasing awareness of bronchiectasis in children and adolescents, a chronic pulmonary disorder associated with poor quality of life for the child/adolescent and their parents, recurrent exacerbations, and costs to the family and health systems. Optimal treatment improves clinical outcomes. Several national guidelines exist, but there are no international guidelines.The European Respiratory Society (ERS) Task Force for the management of paediatric bronchiectasis sought to identify evidence-based management (investigation and treatment) strategies. It used the ERS standardised methodology that included a systematic review of the literature and application of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to define the quality of the evidence and level of recommendations.A multidisciplinary team of specialists in paediatric and adult respiratory medicine, infectious disease, physiotherapy, primary care, nursing, radiology, immunology, methodology, patient advocacy and parents of children/adolescents with bronchiectasis considered the most relevant clinical questions (for both clinicians and patients) related to managing paediatric bronchiectasis. 14 key clinical questions (seven PICO (Patient, Intervention, Comparison, Outcome) and seven narrative) were generated. The outcomes for each PICO were decided by voting by the panel and parent/patient advisory group.This guideline addresses the definition, diagnostic approach and antibiotic treatment of exacerbations, pathogen eradication, long-term antibiotic therapy, asthma-type therapies (inhaled corticosteroids and bronchodilators), mucoactive drugs, airway clearance, investigation of underlying causes of bronchiectasis, disease monitoring, factors to consider before surgical treatment, and the reversibility and prevention of bronchiectasis in children/adolescents. Benchmarking quality of care for children/adolescents with bronchiectasis to improve clinical outcomes and evidence gaps for future research could be based on these recommendations.

Electronic cigarettes: A position statement from the Thoracic Society of Australia and New Zealand.

The TSANZ develops position statements where insufficient data exist to write formal clinical guidelines. In 2018, the TSANZ addressed the question of potential benefits and health impacts of electronic cigarettes (EC). The working party included groups focused on health impacts, smoking cessation, youth issues and priority populations. The 2018 report on the Public Health Consequences of E-Cigarettes from the United States NASEM was accepted as reflective of evidence to mid-2017. A search for papers subsequently published in peer-reviewed journals was conducted in August 2018. A small number of robust and important papers published until March 2019 were also identified and included. Groups identified studies that extended, modified or contradicted the NASEM report. A total of 3793 papers were identified and reviewed, with summaries and draft position statements developed and presented to TSANZ membership in April 2019. After feedback from members and external reviewers, a collection of position statements was finalized in December 2019. EC have adverse lung effects and harmful effects of long-term use are unknown. EC are unsuitable consumer products for recreational use, part-substitution for smoking or long-term exclusive use by former smokers. Smokers who require support to quit smoking should be directed towards approved medication in conjunction with behavioural support as having the strongest evidence for efficacy and safety. No specific EC product can be recommended as effective and safe for smoking cessation. Smoking cessation claims in relation to EC should be assessed by established regulators.

A decade on: Follow-up findings of indigenous children with bronchiectasis.

OBJECTIVE: The sole prospective longitudinal study of children with either chronic suppurative lung disease (CSLD) or bronchiectasis published in the current era was limited to a single center. We sought to extend this study by evaluating the longer-term clinical and lung function outcomes and their associated risk factors in Indigenous children of adolescents from Australia, Alaska, and New Zealand who participated in our previous CSLD or bronchiectasis studies during 2004-2010. METHODS: Between 2015 and 2018, we evaluated 131 out of 180 (72.8%) children of adolescents from the original studies at a single follow-up visit. We administered standardized questionnaires, reviewed medical records, undertook clinical examinations, performed spirometry, and scored available chest computed tomography scans. RESULTS: Participants were seen at a mean age of 12.3 years (standard deviation: 2.6) and a median of 9.0 years (range: 5.0-13.0) after their original recruitment. With increasing age, rates of acute lower respiratory infections (ALRI) declined, while lung function was mostly within population norms (median forced expiry volume in one-second = 90% predicted, interquartile range [IQR]: 81-105; forced vital capacity [FVC] = 98% predicted, IQR: 85-114). However, 43 out of 111 (38.7%) reported chronic cough episodes. Their overall global rating judged by symptoms, including ALRI frequency, examination findings, and spirometry was well (20.3%), stable (43.9%), or improved (35.8%). Multivariable regression identified household tobacco exposure and age at first ALRI-episode as independent risk factors associated with lower FVC% predicted values. CONCLUSION: Under our clinical care, the respiratory outcomes in late childhood or early adolescence are encouraging for these patient populations at high-risk of premature mortality. Prospective studies to further inform management throughout the life course into adulthood are now needed.

Efficacy of oral amoxicillin-clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1): a multicentre, three-arm, double-blind, randomised placebo-controlled trial.

BACKGROUND: Bronchiectasis guidelines recommend antibiotics for the treatment of acute respiratory exacerbations, but randomised placebo-controlled trials in children are lacking. We hypothesised that oral amoxicillin-clavulanate and azithromycin would each be superior to placebo in achieving symptom resolution of non-severe exacerbations in children by day 14 of treatment. METHODS: In this multicentre, three-arm, parallel, double-dummy, double-blind, randomised placebo-controlled trial at four paediatric centres in Australia and New Zealand, we enrolled children aged 1-18 years with CT-confirmed bronchiectasis unrelated to cystic fibrosis, who were under the care of a respiratory physician and who had had at least two respiratory exacerbations in the 18 months before study entry. Participants were allocated (1:1:1) at exacerbation onset to receive oral suspensions of amoxicillin-clavulanate (45 mg/kg per day) plus placebo azithromycin, azithromycin (5 mg/kg per day) plus placebo amoxicillin-clavulanate, or both placebos for 14 days. An independent statistician prepared a computer-generated, permuted-block (size 2-8) randomisation sequence, stratified by centre, age, and cause. Participants, caregivers, study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was the proportion of children with exacerbation resolution by day 14 in the intention-to-treat population. Treatment groups were compared using generalised linear models. Statistical significance was set at p<0·0245 to account for multiple comparisons. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000011886) and is completed. FINDINGS: Between April 17, 2012, and March 1, 2017, 604 children were screened and 252 were enrolled. Between July 31, 2012, and June 26, 2017, 197 children were allocated at the start of an exacerbation (63 to the amoxicillin-clavulanate group, 67 to the azithromycin group, and 67 to the placebo group). Respiratory viruses were identified in 82 (53%) of 154 children with available nasal swabs on day 1 of treatment. Primary outcome data were available for 196 (99%) children (one child with missing data [placebo group] was recorded as non-resolved according to criteria defined a priori). By day 14, exacerbations had resolved in 41 (65%) children in the amoxicillin-clavulanate group, 41 (61%) in the azithromycin group, and 29 (43%) in the placebo group. Compared with placebo, relative risk for resolution by day 14 was 1·50 (95% CI 1·08-2·09, p=0·015; number-needed-to-treat [NNT] 5 [95% CI 3-20]) in the amoxicillin-clavulanate group and 1·41 (1·01-1·97, p=0·042; NNT 6 [3-79]) in the azithromycin group. Adverse events were recorded in 19 (30%) children in the amoxicillin-clavulanate group, 20 (30%) in the azithromycin group, and 14 (21%) in the placebo group, but no events were severe or life-threatening. INTERPRETATION: Amoxicillin-clavulanate treatment is beneficial in terms of resolution of non-severe exacerbations of bronchiectasis in children, and should remain the first-line oral antibiotic in this setting. FUNDING: National Health and Medical Research Council (Australia), Cure Kids (New Zealand).

Clinical course of chronic suppurative lung disease and bronchiectasis in Alaska Native children.

INTRODUCTION: Alaska Native (AN) children from the Yukon Kuskokwim (YK) Delta region have high rates of chronic suppurative lung disease (CSLD), including bronchiectasis. We characterized the clinical progress of an AN adolescent cohort with CSLD/bronchiectasis, and estimated bronchiectasis prevalence trends in this region. METHODS: The original cohort comprised 41 AN children (originally aged 0.5-8 years) with CSLD/bronchiectasis, recruited between 2005 and 2008, with follow-up in 2015-2016. Clinical assessments, lung function, radiography, medical chart review, and spirometry were obtained. We also conducted data queries of bronchiectasis diagnoses in YK individuals born between 1990 and 2010 to estimate prevalence. RESULTS: Thirty-four (83%) of the original cohort aged 7.3-17.6 years were reviewed, of whom 14 (41%) had high-resolution computed tomography (HRCT)-confirmed bronchiectasis, eight (24%) had no evidence of bronchiectasis on HRCT scans, while 12 (35%) had not undergone HRCT scans. Annual lower respiratory tract infection (LRTI) frequency decreased with age, although 27 (79%) still had respiratory symptoms, including all with HRCT-confirmed bronchiectasis, who were also more likely than those without confirmed bronchiectasis to have recent wheeze (80 vs 25%, P = 0.005), auscultatory crackles (60 vs 0%, P < 0.001), and lower mean forced expiratory volume in 1-second/forced vital capacity ratio (73 vs 79%, P = 0.03). The bronchiectasis prevalence for YK AN people born during 2000-2009 was 7 per 1000 births, which was lower than previously reported. CONCLUSION: Despite reduced LRTI frequency, most AN children with CSLD/bronchiectasis had symptoms/signs of underlying lung disease as they entered adolescence. Close clinical follow-up remains essential for managing these patients as they transition to adulthood.

Amoxicillin-clavulanate versus azithromycin for respiratory exacerbations in children with bronchiectasis (BEST-2): a multicentre, double-blind, non-inferiority, randomised controlled trial.

BACKGROUND: Although amoxicillin-clavulanate is the recommended first-line empirical oral antibiotic treatment for non-severe exacerbations in children with bronchiectasis, azithromycin is also often prescribed for its convenient once-daily dosing. No randomised controlled trials involving acute exacerbations in children with bronchiectasis have been published to our knowledge. We hypothesised that azithromycin is non-inferior to amoxicillin-clavulanate for resolving exacerbations in children with bronchiectasis. METHODS: We did this parallel-group, double-dummy, double-blind, non-inferiority randomised controlled trial in three Australian and one New Zealand hospital between April, 2012, and August, 2016. We enrolled children aged 1-19 years with radiographically proven bronchiectasis unrelated to cystic fibrosis. At the start of an exacerbation, children were randomly assigned to oral suspensions of either amoxicillin-clavulanate (22·5 mg/kg, twice daily) and placebo or azithromycin (5 mg/kg per day) and placebo for 21 days. We used permuted block randomisation (stratified by age, site, and cause) with concealed allocation. The primary outcome was resolution of exacerbation (defined as a return to baseline) by 21 days in the per-protocol population, with a non-inferiority margin of -20%. We assessed several secondary outcomes including duration of exacerbation, time to next exacerbation, laboratory, respiratory, and quality-of-life measurements, and microbiology. This trial was registered with the Australian/New Zealand Registry (ACTRN12612000010897). FINDINGS: We screened 604 children and enrolled 236. 179 children had an exacerbation and were assigned to treatment: 97 to amoxicillin-clavulanate, 82 to azithromycin). By day 21, 61 (84%) of 73 exacerbations had resolved in the azithromycin group versus 73 (84%) of 87 in the amoxicillin-clavulanate group. The risk difference showed non-inferiority (-0·3%, 95% CI -11·8 to 11·1). Exacerbations were significantly shorter in the amoxicillin-clavulanate group than in the azithromycin group (median 10 days [IQR 6-15] vs 14 days [8-16]; p=0·014). Adverse events were attributed to the trial medication in 17 (21%) of 82 children in the azithromycin group versus 23 (24%) of 97 in the amoxicillin-clavulanate group (relative risk 0·9, 95% CI 0·5 to 1·5). INTERPRETATION: By 21 days of treatment, azithromycin is non-inferior to amoxicillin-clavulanate for resolving exacerbations in children with non-severe bronchiectasis. In some patients, such as those with penicillin hypersensitivity or those likely to have poor adherence, azithromycin provides another option for treating exacerbations, but must be balanced with risk of treatment failure (within a 20% margin), longer exacerbation duration, and the risk of inducing macrolide resistance. FUNDING: Australian National Health and Medical Research Council.

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.

Defining lower airway bacterial infection in children with chronic endobronchial disorders.

BACKGROUND: Differentiating lower airway bacterial infection from possible upper airway contamination in children with endobronchial disorders undergoing bronchoalveolar lavage (BAL) is important for guiding management. A diagnostic bacterial load threshold based on inflammatory markers has been determined to differentiate infection from upper airway contamination in infants with cystic fibrosis, but not for children with protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD), or bronchiectasis. METHODS: BAL samples from children undergoing bronchoscopy underwent quantitative bacterial culture, cytologic examination, and respiratory virus testing; a subset also had interleukin-8 examined. Geometric means (GMs) of total cell counts (TCCs) and neutrophil counts were plotted by respiratory pathogen bacterial load. Logistic regression determined associations between age, sex, Indigenous status, antibiotic exposure, virus detection and bacterial load, and elevated TCCs (>400 × 103 cells/mL) and airway neutrophilia (neutrophils >15% BAL leukocytes). RESULTS: From 2007 to 2016, 655 children with PBB, CSLD, or bronchiectasis were enrolled. In univariate analyses, Indigenous status and bacterial load ≥105 colony-forming units (CFU)/mL were positively associated with high TCCs. Viruses and bacterial load ≥104 CFU/mL were positively associated with neutrophilia; negative associations were seen for Indigenous status and macrolides. In children who had not received macrolide antibiotics, bacterial load was positively associated in multivariable analyses with high TCCs at ≥104 CFU/mL and with neutrophilia at ≥105 CFU/mL; GMs of TCCs and neutrophil counts were significantly elevated at 104 and 105 CFU/mL compared to negative cultures. CONCLUSIONS: Our findings support a BAL threshold ≥104 CFU/mL to define lower airway infection in children with chronic endobronchial disorders.

Feasibility of a Peer-Led Asthma and Smoking Prevention Project in Australian Schools with High Indigenous Youth.

BACKGROUND: The high global burden of asthma and tobacco smoking among Indigenous people may potentially be reduced by appropriate interventions that target prevention of tobacco smoke uptake and improved asthma management. The latter includes targeted treatment based on airway inflammation. We undertook a feasibility study in two Darwin schools with a high proportion of Indigenous youth to determine the feasibility of an innovative, peer-led, school-based education program called the Asthma and Smoking Prevention Project (ASPP). A subset of children with reported persistent respiratory symptoms were also clinically evaluated to determine the lower airway inflammatory profile and optimize asthma management. METHODS: The ASPP is founded on an evidence-based three-step program and targets improving asthma management and preventing the uptake of tobacco smoking. The program uses a student-centered approach in which senior students (peer leaders) deliver the ASPP to Grade 7 students using activities, videos, and games. Students completed questionnaires related to asthma and smoking at baseline and 3 months after program delivery. Students with respiratory symptoms at 3 months were invited for a comprehensive clinical evaluation and tests including sputum induction. RESULTS: The ASPP was well received. Of the 203 students involved, 56 (28%) were Indigenous and 70% completed baseline and follow-up questionnaires. Self-reported asthma was high (19%), 10% of students reported smoking and 63% reported exposure to tobacco at home. Of the 22 students who were clinically evaluated, 41% were Indigenous. Clinically important airway inflammation was high; 23% had Fractional Exhaled Nitric Oxide Levels ≥35 ppb, 88% had airway neutrophilia (>15%), and 29% had airway eosinophilia (>2.5%). Optimization of medication and management was required in 59% of students. CONCLUSION: Our study has demonstrated the implementation of the ASPP was well received by the schools as well as by the students. The high prevalence of clinically important airway inflammation and suboptimal asthma management highlights the need for a community-based study on persistent respiratory symptoms in adolescents to reduce the burden of chronic lung disease particularly for Indigenous Australians.