Twenty-four Month Outcomes of Extended- Versus Standard-course Antibiotic Therapy in Children Hospitalized With Pneumonia in High-risk Settings: A Randomized Controlled Trial.

BACKGROUND: Pediatric community-acquired pneumonia (CAP) can lead to long-term respiratory sequelae, including bronchiectasis. We determined if an extended (13-14 days) versus standard (5-6 days) antibiotic course improves long-term outcomes in children hospitalized with CAP from populations at high risk of chronic respiratory disease. METHODS: We undertook a multicenter, double-blind, superiority, randomized controlled trial involving 7 Australian, New Zealand, and Malaysian hospitals. Children aged 3 months to ≤5 years hospitalized with radiographic-confirmed CAP who received 1-3 days of intravenous antibiotics, then 3 days of oral amoxicillin-clavulanate, were randomized to either extended-course (8-day oral amoxicillin-clavulanate) or standard-course (8-day oral placebo) arms. Children were reviewed at 12 and 24 months. The primary outcome was children with the composite endpoint of chronic respiratory symptoms/signs (chronic cough at 12 and 24 months; ≥1 subsequent hospitalized acute lower respiratory infection by 24 months; or persistent and/or new chest radiographic signs at 12-months) at 24-months postdischarge, analyzed by intention-to-treat, where children with incomplete follow-up were assumed to have chronic respiratory symptoms/signs ("worst-case" scenario). RESULTS: A total of 324 children were randomized [extended-course (n = 163), standard-course (n = 161)]. For our primary outcome, chronic respiratory symptoms/signs occurred in 97/163 (60%) and 94/161 (58%) children in the extended-courses and standard-courses, respectively [relative risk (RR) = 1.02, 95% confidence interval (CI): 0.85-1.22]. Among children where all sub-composite outcomes were known, chronic respiratory symptoms/signs between groups, RR = 1.10, 95% CI: 0.69-1.76 [extended-course = 27/93 (29%) and standard-course = 24/91 (26%)]. Additional sensitivity analyses also revealed no between-group differences. CONCLUSION: Among children from high-risk populations hospitalized with CAP, 13-14 days of antibiotics (versus 5-6 days), did not improve long-term respiratory outcomes.

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.

Chronic respiratory disease in Indigenous peoples: a framework to address inequity and strengthen respiratory health and health care globally.

Indigenous peoples around the world bear a disproportionate burden of chronic respiratory diseases, which are associated with increased risks of morbidity and mortality. Despite the imperative to address global inequity, research focused on strengthening respiratory health in Indigenous peoples is lacking, particularly in low-income and middle-income countries. Drivers of the increased rates and severity of chronic respiratory diseases in Indigenous peoples include a high prevalence of risk factors (eg, prematurity, low birthweight, poor nutrition, air pollution, high burden of infections, and poverty) and poor access to appropriate diagnosis and care, which might be linked to colonisation and historical and current systemic racism. Efforts to tackle this disproportionate burden of chronic respiratory diseases must include both global approaches to address contributing factors, including decolonisation of health care and research, and local approaches, co-designed with Indigenous people, to ensure the provision of culturally strengthened care with more equitable prioritisation of resources. Here, we review evidence on the burden of chronic respiratory diseases in Indigenous peoples globally, summarise factors that underlie health disparities between Indigenous and non-Indigenous people, propose a framework of approaches to improve the respiratory health of Indigenous peoples, and outline future directions for clinical care and research.

Thoracic Society of Australia and New Zealand (TSANZ) position statement on chronic suppurative lung disease and bronchiectasis in children, adolescents and adults in Australia and New Zealand.

This position statement, updated from the 2015 guidelines for managing Australian and New Zealand children/adolescents and adults with chronic suppurative lung disease (CSLD) and bronchiectasis, resulted from systematic literature searches by a multi-disciplinary team that included consumers. The main statements are: Diagnose CSLD and bronchiectasis early; this requires awareness of bronchiectasis symptoms and its co-existence with other respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease). Confirm bronchiectasis with a chest computed-tomography scan, using age-appropriate protocols and criteria in children. Undertake a baseline panel of investigations. Assess baseline severity, and health impact, and develop individualized management plans that include a multi-disciplinary approach and coordinated care between healthcare providers. Employ intensive treatment to improve symptom control, reduce exacerbation frequency, preserve lung function, optimize quality-of-life and enhance survival. In children, treatment also aims to optimize lung growth and, when possible, reverse bronchiectasis. Individualize airway clearance techniques (ACTs) taught by respiratory physiotherapists, encourage regular exercise, optimize nutrition, avoid air pollutants and administer vaccines following national schedules. Treat exacerbations with 14-day antibiotic courses based upon lower airway culture results, local antibiotic susceptibility patterns, clinical severity and patient tolerance. Patients with severe exacerbations and/or not responding to outpatient therapy are hospitalized for further treatments, including intravenous antibiotics and intensive ACTs. Eradicate Pseudomonas aeruginosa when newly detected in lower airway cultures. Individualize therapy for long-term antibiotics, inhaled corticosteroids, bronchodilators and mucoactive agents. Ensure ongoing care with 6-monthly monitoring for complications and co-morbidities. Undertake optimal care of under-served peoples, and despite its challenges, delivering best-practice treatment remains the overriding aim.

Extended Versus Standard Antibiotic Course Duration in Children <5 Years of Age Hospitalized With Community-acquired Pneumonia in High-risk Settings: Four-week Outcomes of a Multicenter, Double-blind, Parallel, Superiority Randomized Controlled Trial.

BACKGROUND: High-level evidence is limited for antibiotic duration in children hospitalized with community-acquired pneumonia (CAP) from First Nations and other at-risk populations of chronic respiratory disorders. As part of a larger study, we determined whether an extended antibiotic course is superior to a standard course for achieving clinical cure at 4 weeks in children 3 months to ≤5 years old hospitalized with CAP. METHODS: In our multinational (Australia, New Zealand, Malaysia), double-blind, superiority randomized controlled trial, children hospitalized with uncomplicated, radiographic-confirmed, CAP received 1-3 days of intravenous antibiotics followed by 3 days of oral amoxicillin-clavulanate (80 mg/kg, amoxicillin component, divided twice daily) and then randomized to extended (13-14 days duration) or standard (5-6 days) antibiotics. The primary outcome was clinical cure (complete resolution of respiratory symptoms/signs) 4 weeks postenrollment. Secondary outcomes included adverse events, nasopharyngeal bacterial pathogens and antimicrobial resistance at 4 weeks. RESULTS: Of 372 children enrolled, 324 fulfilled the inclusion criteria and were randomized. Using intention-to-treat analysis, between-group clinical cure rates were similar (extended course: n = 127/163, 77.9%; standard course: n = 131/161, 81.3%; relative risk = 0.96, 95% confidence interval = 0.86-1.07). There were no significant between-group differences for adverse events (extended course: n = 43/163, 26.4%; standard course, n = 32/161, 19.9%) or nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus or antimicrobial resistance. CONCLUSIONS: Among children hospitalized with pneumonia and at-risk of chronic respiratory illnesses, an extended antibiotic course was not superior to a standard course at achieving clinical cure at 4 weeks. Additional research will identify if an extended course provides longer-term benefits.

Long-term outcomes of adults with acute respiratory failure treated with veno-venous extracorporeal membrane oxygenation.

Veno-venous extracorporeal membrane oxygenation is increasingly used for severe but potentially reversible acute respiratory failure in adults; however, there are limited data regarding long-term morbidity. At our institution, most patients requiring veno-venous extracorporeal membrane oxygenation have been followed up by a single physician. Our primary aim was to describe the serial long-term morbidity for respiratory, musculoskeletal and psychological functioning.A retrospective audit of inpatient and outpatient medical records was conducted. A total of 125 patients treated with veno-venous extracorporeal membrane oxygenation for primary respiratory failure were included. The patients were young (mean (standard deviation) age 43.7 (4.1) years), obese (mean (standard deviation) body mass index 30.8 (10.4) kg/m2), and mostly were male (59%). Most patients (60%) had no comorbidities.The survival rate to discharge was 70%, with body mass index and the number of comorbidities being independent predictors of survival on multiple logistic regression analysis. Over half (57%) of the Australian survivors had regular outpatient follow-up. They had a median of three reviews (range 1-9) over a median of 11.8 months (range 1.5-79) months. Breathlessness and weakness resolved in most within six months, with lung function abnormalities taking longer to resolve. Over half (60%) returned to employment within six months of discharge. Over a quarter (29%) displayed symptoms of anxiety, depression or post-traumatic stress disorder.

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.

Otitis media guidelines for Australian Aboriginal and Torres Strait Islander children: summary of recommendations.

INTRODUCTION: The 2001 Recommendations for clinical care guidelines on the management of otitis media in Aboriginal and Torres Islander populations were revised in 2010. This 2020 update by the Centre of Research Excellence in Ear and Hearing Health of Aboriginal and Torres Strait Islander Children used for the first time the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. MAIN RECOMMENDATIONS: We performed systematic reviews of evidence across prevention, diagnosis, prognosis and management. We report ten algorithms to guide diagnosis and clinical management of all forms of otitis media. The guidelines include 14 prevention and 37 treatment strategies addressing 191 questions. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINES: A GRADE approach is used. Targeted recommendations for both high and low risk children. New tympanostomy tube otorrhoea section. New Priority 5 for health services: annual and catch-up ear health checks for at-risk children. Antibiotics are strongly recommended for persistent otitis media with effusion in high risk children. Azithromycin is strongly recommended for acute otitis media where adherence is difficult or there is no access to refrigeration. Concurrent audiology and surgical referrals are recommended where delays are likely. Surgical referral is recommended for chronic suppurative otitis media at the time of diagnosis. The use of autoinflation devices is recommended for some children with persistent otitis media with effusion. Definitions for mild (21-30 dB) and moderate (> 30 dB) hearing impairment have been updated. New "OMapp" enables free fast access to the guidelines, plus images, animations, and multiple Aboriginal and Torres Strait Islander language audio translations to aid communication with families.

Study Protocol for Preventing Early-Onset Pneumonia in Young Children Through Maternal Immunisation: A Multi-Centre Randomised Controlled Trial (PneuMatters).

Background: Preventing and/or reducing acute lower respiratory infections (ALRIs) in young children will lead to substantial short and long-term clinical benefits. While immunisation with pneumococcal conjugate vaccines (PCV) reduces paediatric ALRIs, its efficacy for reducing infant ALRIs following maternal immunisation has not been studied. Compared to other PCVs, the 10-valent pneumococcal-Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV) is unique as it includes target antigens from two common lower airway pathogens, pneumococcal capsular polysaccharides and protein D, which is a conserved H. influenzae outer membrane lipoprotein. Aims: The primary aim of this randomised controlled trial (RCT) is to determine whether vaccinating pregnant women with PHiD-CV (compared to controls) reduces ALRIs in their infants' first year of life. Our secondary aims are to evaluate the impact of maternal PHiD-CV vaccination on different ALRI definitions and, in a subgroup, the infants' nasopharyngeal carriage of pneumococci and H. influenzae, and their immune responses to pneumococcal vaccine type serotypes and protein D. Methods: We are undertaking a parallel, multicentre, superiority RCT (1:1 allocation) at four sites across two countries (Australia, Malaysia). Healthy pregnant Australian First Nation or Malaysian women aged 17-40 years with singleton pregnancies between 27+6 and 34+6 weeks gestation are randomly assigned to receive either a single dose of PHiD-CV or usual care. Treatment allocation is concealed. Study outcome assessors are blinded to treatment arms. Our primary outcome is the rate of medically attended ALRIs by 12-months of age. Blood and nasopharyngeal swabs are collected from infants at birth, and at ages 6- and 12-months (in a subset). Our planned sample size (n = 292) provides 88% power (includes 10% anticipated loss to follow-up). Discussion: Results from this RCT potentially leads to prevention of early and recurrent ALRIs and thus preservation of lung health during the infant's vulnerable period when lung growth is maximum. The multicentre nature of our study increases the generalisability of its future findings and is complemented by assessing the microbiological and immunological outcomes in a subset of infants. Clinical Trial Registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374381, identifier: ACTRN12618000150246.

Cryobiopsy for Identification of Usual Interstitial Pneumonia and Other Interstitial Lung Disease Features. Further Lessons from COLDICE, a Prospective Multicenter Clinical Trial.

Rationale: Transbronchial lung cryobiopsy (TBLC) is an emerging technique for interstitial lung disease diagnosis. Good histopathologic agreement between TBLC and surgical lung biopsy (SLB) was demonstrated in the COLDICE (Cryobiopsy versus Open Lung Biopsy in the Diagnosis of Interstitial Lung Disease Alliance) study; however, diagnostic confidence was frequently lower for TBLC than SLB. Objectives: To characterize specific features of TBLC predictive of usual interstitial pneumonia (UIP) in corresponding SLB and to identify clinical indices predictive of biopsy concordance. Methods: The COLDICE study was a prospective, multicenter study investigating diagnostic agreement between TBLC and SLB. The participants underwent both procedures with blinded pathologist analysis of specimens, applying international guideline criteria. The TBLC features predictive of UIP in the paired SLB and predictive features of overall concordance were analyzed. Measurements and Main Results: A total of 65 patients (66.1 ± 9.3 yr; FVC, 84.7 ± 14.2%; DlCO, 63.4 ± 13.8%) participated in the COLDICE study. UIP was identified in 33/65 (50.8%) SLB, and 81.5% were concordant with corresponding TBLC (κ, 0.61; 95% confidence interval [CI], 0.38-0.77). The UIP guideline criteria of "predominantly subpleural or paraseptal fibrosis" was infrequently reported in TBLC (8/33, 24.2%), whereas "patchy fibrosis," "fibroblast foci," and the "absence of alternative diagnostic features" were frequently observed in TBLC. The combination of these three features strongly predicted UIP in paired SLB (odds ratio [OR], 23.4; 95% CI, 6.36-86.1; P < 0.0001). Increased numbers of TBLC samples predicted histopathologic concordance with SLB (OR, 1.8; 95% CI, 1.08-3.01; P = 0.03). The predictors of discordance included older age, family history, and radiologic asymmetry. Conclusions: Subpleural and/or paraseptal fibrosis were not essential for diagnosing UIP in TBLC, provided that other guideline criteria features were present. The diagnostic accuracy of TBLC was strengthened when increased numbers of samples were taken. Clinical trial registered with www.anzctr.org.au (ACTRN12615000718549).

Priorities and expectations of patients attending a multidisciplinary interstitial lung disease clinic.

BACKGROUND AND OBJECTIVE: The significant and progressive morbidity associated with ILD mean that patients often struggle with the impact of this disease on their QOL and independence. To date, no studies have investigated the importance of multidisciplinary care on patient experience in ILD. We aimed to determine the expectations and priorities of patients attending a tertiary referral centre multidisciplinary ILD clinic. In particular, we sought to learn how important the multidisciplinary element of the clinic was to patients and which aspects of the clinic were most valued. METHODS: An 18-item patient questionnaire was developed in conjunction with expert physicians and specialist nurses involved in the ILD clinic and sent to all patients on the centre's ILD registry at the time of the study (n = 240). Patients rated the importance of different aspects of their experience of attending the clinic. Data collected were analysed using descriptive statistics. Comparisons across disease severity were made using two-sided Z-tests for independent proportions. RESULTS: A total of 100 respondents comprised the study group. Almost all respondents valued the multidisciplinary aspect of the clinic. Obtaining an accurate diagnosis and improving their disease understanding was most important to respondents. The importance of the ILD specialist nurse for both education and support increased with worsening disease severity. CONCLUSION: Our results suggest that a multidisciplinary approach to the management of ILD with additional focus on patient education, as well as tailoring care to disease severity, is a plausible pathway to improving the patient experience with ILD.

Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung disease diagnosis (COLDICE): a prospective, comparative study.

BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is a novel technique for sampling lung tissue for interstitial lung disease diagnosis. The aim of this study was to establish the diagnostic accuracy of TBLC compared with surgical lung biopsy (SLB), in the context of increasing use of TBLC in clinical practice as a less invasive biopsy technique. METHODS: COLDICE was a prospective, multicentre, diagnostic accuracy study investigating diagnostic agreement between TBLC and SLB, across nine Australian tertiary hospitals. Patients with interstitial lung disease aged between 18 and 80 years were eligible for inclusion if they required histopathological evaluation to aid diagnosis, after detailed baseline evaluation. After screening at a centralised multidisciplinary discussion (MDD), patients with interstitial lung disease referred for lung biopsy underwent sequential TBLC and SLB under one anaesthetic. Each tissue sample was assigned a number between 1 and 130, allocated in a computer-generated random sequence. Encoded biopsy samples were then analysed by masked pathologists. At subsequent MDD, de-identified cases were discussed twice with either TBLC or SLB along with clinical and radiological data, in random non-consecutive order. Co-primary endpoints were agreement of histopathological features in TBLC and SLB for patterns of definite or probable usual interstitial pneumonia, indeterminate for usual interstitial pneumonia, and alternative diagnosis; and for agreement of consensus clinical diagnosis using TBLC and SLB at MDD. Concordance and κ values were calculated for each primary endpoint. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12615000718549. FINDINGS: Between March 15, 2016, and April 15, 2019, we enrolled 65 patients (31 [48%] men, 34 [52%] women; mean age 66·1 years [SD 9·3]; forced vital capacity 83·7% [SD 14·2]; diffusing capacity for carbon monoxide 63·4% [SD 12·8]). TBLC (7·1 mm, SD 1·9) and SLB (46·5 mm, 14·9) samples were each taken from two separate ipsilateral lobes. Histopathological agreement between TBLC and SLB was 70·8% (weighted κ 0·70, 95% CI 0·55-0·86); diagnostic agreement at MDD was 76·9% (κ 0·62, 0·47-0·78). For TBLC with high or definite diagnostic confidence at MDD (39 [60%] of 65 cases), 37 (95%) were concordant with SLB diagnoses. In the 26 (40%) of 65 cases with low-confidence or unclassifiable TBLC diagnoses, SLB reclassified six (23%) to alternative high-confidence or definite MDD diagnoses. Mild-moderate airway bleeding occurred in 14 (22%) patients due to TBLC. The 90-day mortality was 2% (one of 65 patients), following acute exacerbation of idiopathic pulmonary fibrosis. INTERPRETATION: High levels of agreement between TBLC and SLB for both histopathological interpretation and MDD diagnoses were shown. The TBLC MDD diagnoses made with high confidence were particularly reliable, showing excellent concordance with SLB MDD diagnoses. These data support the clinical utility of TBLC in interstitial lung disease diagnostic algorithms. Further studies investigating the safety profile of TBLC are needed. FUNDING: University of Sydney, Hunter Medical Research Institute, Erbe Elektromedizin, Medtronic, Cook Medical, Rymed, Karl-Storz, Zeiss, and Olympus.

Effectiveness of a chronic cough management algorithm at the transitional stage from acute to chronic cough in children: a multicenter, nested, single-blind, randomised controlled trial.

BACKGROUND: Chronic (lasting at least 4 weeks) cough in children is an important cause of morbidity. An algorithmic approach to the management of coughs in children evaluated in observational studies and a randomised controlled trial (RCT) enrolled children referred with median cough duration of 16 weeks to specialist centres. We investigated whether applying an evidence-based cough management algorithm in non-specialist settings earlier, once cough persisted for more than 4 weeks, improved cough resolution compared with usual care. METHODS: We undertook a multicentre, single-blind RCT nested within a prospective cohort study of children (<15 years) in Australia presenting to three primary care or three hospital emergency departments with an acute respiratory illness with cough. Children were excluded if they had a known diagnosis of an underlying chronic medical condition (excluding asthma) or had an immunosuppressive illness or were taking immunomodulating drugs for more than 2 weeks in the preceding 30 days, or had severe symptoms requiring inpatient hospitalisation. Children were followed up for 8 weeks; those with a persistent cough at day 28 were randomly assigned to the cough management algorithm or to usual care. Randomisation was stratified by reason for presentation, study site, and cough duration (4 weeks to <6 weeks vs ≥6 weeks) using computer-generated permuted blocks (block size of four) with a 1:1 allocation. The primary outcome was the proportion of children with cough resolution at day 56 (defined as resolved if the child did not cough for at least 3 days and nights since day 28 or a more than 75% reduction in their average day and night cough score). Absolute risk differences (RDabsolute) were calculated by modified intention-to-treat analysis (ITT). This trial is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12615000132549. FINDINGS: Between July 7, 2015, and Oct 31, 2018, 1018 children were screened, 509 were enrolled in the cohort study, and of 115 children in the ITT analysis, 57 were randomly assigned to the intervention group and 58 to the control group. Children had a median age of 1·6 years (IQR 1·0-4·5); 45 (39%) of 115 were Indigenous, and 59 (51%) were boys. By day 56, 33 (58%) of 57 children in the intervention group achieved cough resolution compared with 23 (40%) 58 in the control group; cough resolution was unknown in 12 (21%) of 57 children receiving the intervention and in 13 (22%) of 58 receiving the control. The RDabsolute assuming children with an unknown cough outcome were still coughing at day 56 was 18·3% (95% CI 0·3-36·2); the number needed-to-treat for benefit was five (95% CI 3-364); the adjusted odds ratio was 1·5 (95% CI 1·3-1·6), favouring the intervention group. INTERPRETATION: This study suggests an evidence-based cough management algorithm improves cough resolution in community-based children in the early phases of chronic cough. However, larger studies to confirm these findings in primary care are required. FUNDING: National Health and Medical Research Council.

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).

Cryobiopsy versus open lung biopsy in the diagnosis of interstitial lung disease (COLDICE): protocol of a multicentre study.

Introduction: Transbronchial lung cryobiopsy (TBLC) is a novel, minimally invasive technique for obtaining lung tissue for histopathological assessment in interstitial lung disease (ILD). Despite its increasing popularity, the diagnostic accuracy of TBLC is not yet known. The COLDICE Study (Cryobiopsy versus Open Lung biopsy in the Diagnosis of Interstitial lung disease allianCE) aims to evaluate the agreement between TBLC and surgical lung biopsy sampled concurrently from the same patients, for both histopathological and multidisciplinary discussion (MDD) diagnoses. Methods and analysis: This comparative, multicentre, prospective trial is enrolling patients with ILD requiring surgical lung biopsy to aid with their diagnosis. Participants are consented for both video-assisted thoracoscopic surgical (VATS) biopsy and TBLC within the same anaesthetic episode. Specimens will be blindly assessed by three expert pathologists both individually and by consensus. Each tissue sample will then be considered in conjunction with clinical and radiological data, within a centralised MDD. Each patient will be presented twice in random order, once with TBLC data and once with VATS data. Meeting participants will be blinded to the method of tissue sampling. The accuracy of TBLC will be assessed by agreement with VATS at (1) histopathological analysis and (2) MDD diagnosis. Data will be collected on interobserver agreement between pathologists, interobserver agreement between MDD participants, and detailed clinical and procedural characteristics. Ethics and dissemination: The study is being conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice and Australian legislation for the ethical conduct of research. Trial registration number: ACTRN12615000718549.

Nocturnal hypoxaemia is associated with adverse outcomes in interstitial lung disease.

BACKGROUND AND OBJECTIVE: Sleep-disordered breathing (SDB) has been reported as highly prevalent in idiopathic pulmonary fibrosis (IPF) and other interstitial lung disease (ILD) populations. Nocturnal oxygen desaturation (NOD), or the total sleep time spent with SpoO2 < 90% (TST < 90), can occur both with and without associated apnoeas, and is common in ILD. This study aimed to characterize abnormal SDB and extent of TST < 90 in ILD patients and evaluate relationships between TST < 90 and markers of disease severity, development of pulmonary hypertension (PH) and mortality. METHODS: Consecutive, newly referred ILD patients attending a specialist clinic underwent polysomnography (PSG). Serial lung function tests, echocardiography and other clinical variables were recorded. Predictors of PH and mortality were evaluated using logistic regression and Cox proportional hazards regression analyses. RESULTS: A total of 92 ILD patients (including 44 with IPF) underwent PSG. At least mild obstructive sleep apnoea (OSA) was observed in 65.2%, with rapid eye movement (REM)-related events occurring frequently. At least 10% TST < 90 (designated 'significant NOD') was present in 35.9% of patients, and was associated with PH at baseline echocardiography. Multiple indices of hypoxaemia during sleep, including significant NOD, predicted the development of new or worsening PH. TST < 90 predicted overall and progression-free survival. CONCLUSION: Nocturnal oxygen saturation is associated with poorer prognosis in ILD patients and may contribute towards the pathogenesis of pulmonary vascular disease.

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.