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.

Thoracic Society of Australia and New Zealand position statement: The safe clinical use of sputum induction for bio-sampling of the lower airways in children and adults.

Sputum induction is widely used in clinical settings for collection of biological samples from the lower airways. However, in recent years sputum induction has been associated with serious adverse events and even death. This position statement was commissioned by the Thoracic Society of Australia and New Zealand to address major adverse events of two deaths associated with sputum induction that have occurred in Australia in 2021, and outlines best practice for the safe use of sputum induction. The statement resulted from systematic literature searches by a multi-disciplinary group including respiratory physicians, nurses and physiotherapists (paediatric and adults focused). Consumers had input to an advanced draft of the position statement. The position statement covers indications for sputum induction, informed consent, scope of practice of personnel administering the procedure, infection control considerations, details about the sputum induction procedure, safety considerations and risk assessment in clinical settings.

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.

Structural Insights into Antibacterial Payload Release from Gold Nanoparticles Bound to E. coli Peptide Deformylase.

The lack of new antibiotics and the rapidly rising number of pathogens resistant to antibiotics pose a serious problem to mankind. In bacteria, the cell membrane provides the first line of defence to antibiotics by preventing them from reaching their molecular target. To overcome this entrance barrier, it has been suggested[1] that small Gold-Nanoparticles (AuNP) could possibly function as drug delivery systems for antibiotic ligands. Using actinonin-based ligands, we provide here proof-of-principle of AuNP functionalisation, the capability to bind and inhibit the target protein of the ligand, and the possibility to selectively release the antimicrobial payload. To this end, we successfully synthesised AuNP coated with thio-functionalised actinonin and a derivative. Interactions between 15N-enriched His-peptide deformylase 1-147 from E. coli (His-ecPDF 1-147) and compound-coated AuNP were investigated via 2D 1H-15N-HSQC NMR spectra proving the direct binding to His-ecPDF 1-147. More importantly by adding dithiothreitol (DTT), we show that the derivative is successfully released from AuNPs while still bound to His-ecPDF 1-147. Our findings indicate that AuNP-conjugated ligands can address and bind intracellular target proteins. The system introduced here presents a new delivery platform for antibiotics and allows for the easy optimisation of ligand coated AuNPs.

Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1-4. Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq5, we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential.

Cough in Children and Adults: Diagnosis, Assessment and Management (CICADA). Summary of an updated position statement on chronic cough in Australia.

INTRODUCTION: Cough is the most common symptom leading to medical consultation. Chronic cough results in significant health care costs, impairs quality of life, and may indicate the presence of a serious underlying condition. Here, we present a summary of an updated position statement on cough management in the clinical consultation. MAIN RECOMMENDATIONS: Assessment of children and adults requires a focused history of chronic cough to identify any red flag cough pointers that may indicate an underlying disease. Further assessment with examination should include a chest x-ray and spirometry (when age > 6 years). Separate paediatric and adult diagnostic management algorithms should be followed. Management of the underlying condition(s) should follow specific disease guidelines, as well as address adverse environmental exposures and patient/carer concerns. First Nations adults and children should be considered a high risk group. The full statement from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia for managing chronic cough is available at https://lungfoundation.com.au/resources/cicada-full-position-statement. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: Algorithms for assessment and diagnosis of adult and paediatric chronic cough are recommended. High quality evidence supports the use of child-specific chronic cough management algorithms to improve clinical outcomes, but none exist in adults. Red flags that indicate serious underlying conditions requiring investigation or referral should be identified. Early and effective treatment of chronic wet/productive cough in children is critical. Culturally specific strategies for facilitating the management of chronic cough in First Nations populations should be adopted. If the chronic cough does not resolve or is unexplained, the patient should be referred to a respiratory specialist or cough clinic.

The SPEC score-A quantifiable CT scoring system for primary ciliary dyskinesia.

BACKGROUND: Structural lung changes seen on computed tomography (CT) scans in persons with primary ciliary dyskinesia (pwPCD) are currently described using cystic fibrosis (CF) derived scoring systems. Recent work has shown structural changes and frequencies that are unique to PCD, indicating the need for a unique PCD-derived scoring system. METHODS: Chest CT scans from 30 pwPCD, were described for structural changes including bronchiectasis, bronchial wall thickening, mucous plugging, atelectasis, air trapping, and interlobar septal thickening and, additionally, changes previously described as being frequent in pwPCD including extensive tree-in-bud pattern of mucous plugging, bronchoceles or nodules, thickening of interlobar and interlobular septa and whole lobe atelectasis. Based on these findings a novel and unique scoring system, the Specific PCD Evaluation by CT (SPEC) score was constructed. Scans were then re-scored using the SPEC score and results compared to corresponding measurements of lung function to assess structure-function correlation. RESULTS: Total SPEC scores ranged from 0 to 60 (max possible score 90). There was a strong negative correlation between the SPEC score (SPEC) and forced vital capacity (FVC), forced expiratory volume over 1 s (FEV1 ) and FEV1 /FVC ratio (-r = .784, -.865, -.872 respectively). CONCLUSIONS: Using PCD-derived data we describe the construct of a PCD-specific score for assessing lung structural damage on CT scans, the SPEC score. A strong correlation between the SPEC score and PFT variables was identified. The SPEC score holds the potential for describing longitudinal changes in CT scans and assessing the efficacy of interventive therapies in patients with PCD.

Evaluation of the implementation and clinical effects of an intervention to improve medical follow-up and health outcomes for Aboriginal children hospitalised with chest infections.

Background: Aboriginal children hospitalised with acute lower respiratory infections (ALRIs) are at-risk of developing bronchiectasis, which can progress from untreated protracted bacterial bronchitis, often evidenced by a chronic (>4 weeks) wet cough following discharge. We aimed to facilitate follow-up for Aboriginal children hospitalised with ALRIs to provide optimal management and improve their respiratory health outcomes. Methods: We implemented an intervention to facilitate medical follow-up four weeks after hospital discharge from a paediatric hospital in Western Australia. The intervention included six-core components that focused on parents, hospital staff and hospital processes. Both health and implementation outcomes were measured for children grouped by three distinct temporal periods of recruitment: (i) nil-intervention, recruited after hospital admission; (ii) health-information only, received during recruitment at hospital admission, pre-intervention; (iii) post-intervention. The primary outcome was the cough-specific quality-of-life score (PC-QoL) in children with a chronic wet cough following discharge. Findings: Of the 214 patients that were recruited, 181 completed the study. Follow-up rates one-month post-discharge were higher in the post-intervention (50.7%) than the nil-intervention (13.6%) and health-information (17.1%) groups. PC-QoL in children with a chronic wet cough was also improved in the post-intervention group compared the health information and nil-intervention groups (difference in means between nil-intervention and post-intervention groups = 1.83, 95% CI: 0.75, 2.92, p = 0.002), aligning with an increase in the percentage who received evidence-based treatment, namely antibiotics at one-month post-discharge (57.9% versus 13.3%). Interpretation: Implementation of our co-designed intervention to facilitate effective and timely medical follow-up for Aboriginal children hospitalised with ALRIs improved their respiratory health outcomes. Funding: State, national grants and fellowships.

Learning to make a difference for chILD: Value creation through network collaboration and team science.

Addressing the recognized challenges and inequalities in providing high quality healthcare for rare diseases such as children's interstitial lung disease (chILD) requires collaboration across institutional, geographical, discipline, and system boundaries. The Children's Interstitial Lung Disease Respiratory Network of Australia and New Zealand (chILDRANZ) is an example of a clinical network that brings together multidisciplinary health professionals for collaboration, peer learning, and advocacy with the goal of improving the diagnosis and management of this group of rare and ultra-rare conditions. This narrative review explores the multifaceted benefits arising from social learning spaces within rare disease clinical networks by applying the value creation framework. The operation of the chILDRANZ network is used as an example across the framework to highlight how value is generated, realized, and transferred within such collaborative clinical and research networks. The community of practice formed in the chILDRANZ multidisciplinary meetings provides a strong example of social learning that engages with the uncertainty inherent in rare disease diagnosis and management and pays attention to generate new knowledge and best practice to make a difference for children and families living with chILD. This review underscores international calls for further investment in, and support of, collaborative clinical networks and virtual centers of excellence for rare disease.

BEAT CF pulmonary exacerbations core protocol for evaluating the management of pulmonary exacerbations in people with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a rare, inherited, life-limiting condition predominantly affecting the lungs, for which there is no cure. The disease is characterized by recurrent pulmonary exacerbations (PEx), which are thought to drive progressive lung damage. Management of these episodes is complex and generally involves multiple interventions targeting different aspects of disease. The emergence of innovative trials and use of Bayesian statistical methods has created renewed opportunities for studying heterogeneous populations in rare diseases. Here, we present the protocol for the BEAT CF PEx cohort, a prospective, multi-site, perpetual, platform enrolling adults and children with CF. The BEAT CF PEx cohort will be used to evaluate the comparative effectiveness of interventions for the treatment of PEx requiring intensive therapy (PERITs), with a primary focus on short-term improvements in lung function. This will be achieved through the conduct of cohort-nested studies, including adaptive clinical trials, within the BEAT CF PEx cohort. This protocol will outline key features of the BEAT CF PEx cohort, including the design, implementation, data collection and management, governance and analysis, and dissemination of results. METHODS: This platform will be conducted across multiple sites, commencing with CF treatment centers in Australia. People of all ages with a clinical diagnosis of CF will be eligible to participate, except those who have previously received a lung transplant. Data including demographic and clinical information, treatment details, and outcomes (including safety, microbiology, and patient-reported outcome measures including quality of life scores) will be systematically collected and securely stored via a digital centralized trial management system (CTMS). The primary endpoint is the absolute change in the percentage predicted forced expiratory volume in 1 s (ppFEV1) from the commencement of intensive therapy to 7 to 10 days afterwards. DISCUSSION: The BEAT CF PEx cohort will report clinical, treatment, and outcome data for PEx among people with CF and is intended to serve as a core (master) protocol for future nested, interventional trials evaluating treatment(s) for these episodes. The protocols for nested sub-studies are beyond the scope of this document and will be reported separately. TRIAL REGISTRATION: ANZCTR BEAT CF Platform - ACTRN12621000638831. Registration date: Sept. 26, 2022.

Spring-infusors: How a simple and small solution can create king-sized complexity.

AIM: The aims of the study were to investigate family and hospital staff views about the use of spring-infusor devices for administration of intravenous antibiotic medications, to examine if the device is acceptable and feasible and to map a process for implementation. DESIGN: A qualitative study with a pragmatist approach, within a larger, mixed methods knowledge translation study. METHODS: Data were collected by semi-structured interviews with patients who have cystic fibrosis and their parents and focus groups and interviews with hospital staff. Interviews were concluded when no new themes were identified. Thematic analysis and process mapping was undertaken. RESULTS: Six parents, nine children and 30 staff were interviewed. Families preferred spring-infusors. Staff knowledge, experience and attitudes toward spring-infusor use was varied. All staff acknowledged that their role is to support patient-centred care. Spring-infusors are preferred by families and clinicians above other IV administration devices but misconceptions about spring-infusor use and numerous procedural challenges reduced their use.

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.

Survival of people with cystic fibrosis in Australia.

Survival statistics, estimated using data from national cystic fibrosis (CF) registries, inform the CF community and monitor disease progression. This study aimed to estimate survival among people with CF in Australia and to identify factors associated with survival. This population-based cohort study used prospectively collected data from 23 Australian CF centres participating in the Australian CF Data Registry (ACFDR) from 2005-2020. Period survival analysis was used to calculate median age of survival estimates for each 5-year window from 2005-2009 until 2016-2020. The overall median survival was estimated using the Kaplan-Meier method. Between 2005-2020 the ACFDR followed 4,601 people with CF, noting 516 (11.2%) deaths including 195 following lung transplantation. Out of the total sample, more than half (52.5%) were male and 395 (8.6%) had undergone lung transplantation. Two thirds of people with CF (66.1%) were diagnosed before six weeks of age or by newborn/prenatal screening. The overall median age of survival was estimated as 54.0 years (95% CI: 51.0-57.04). Estimated median survival increased from 48.9 years (95% CI: 44.7-53.5) for people with CF born in 2005-2009, to 56.3 years (95% CI: 51.2-60.4) for those born in 2016-2020. Factors independently associated with reduced survival include receiving a lung transplant, having low FEV1pp and BMI. Median survival estimates are increasing in CF in Australia. This likely reflects multiple factors, including newborn screening, improvement in diagnosis, refinements in CF management and centre-based multidisciplinary care.

Monitoring disease progression in childhood bronchiectasis.

Bronchiectasis (not related to cystic fibrosis) is a chronic lung disease caused by a range of etiologies but characterized by abnormal airway dilatation, recurrent respiratory symptoms, impaired quality of life and reduced life expectancy. Patients typically experience episodes of chronic wet cough and recurrent pulmonary exacerbations requiring hospitalization. Early diagnosis and management of childhood bronchiectasis are essential to prevent respiratory decline, optimize quality of life, minimize pulmonary exacerbations, and potentially reverse bronchial disease. Disease monitoring potentially allows for (1) the early detection of acute exacerbations, facilitating timely intervention, (2) tracking the rate of disease progression for prognostic purposes, and (3) quantifying the response to therapies. This narrative review article will discuss methods for monitoring disease progression in children with bronchiectasis, including lung imaging, respiratory function, patient-reported outcomes, respiratory exacerbations, sputum biomarkers, and nutritional outcomes.

The role of exome sequencing in childhood interstitial or diffuse lung disease.

BACKGROUND: Children's interstitial and diffuse lung disease (chILD) is a complex heterogeneous group of lung disorders. Gene panel approaches have a reported diagnostic yield of ~ 12%. No data currently exist using trio exome sequencing as the standard diagnostic modality. We assessed the diagnostic utility of using trio exome sequencing in chILD. We prospectively enrolled children meeting specified clinical criteria between 2016 and 2020 from 16 Australian hospitals. Exome sequencing was performed with analysis of an initial gene panel followed by trio exome analysis. A subset of critically ill infants underwent ultra-rapid trio exome sequencing as first-line test. RESULTS: 36 patients [median (range) age 0.34 years (0.02-11.46); 11F] were recruited from multiple States and Territories. Five patients had clinically significant likely pathogenic/pathogenic variants (RARB, RPL15, CTCF, RFXANK, TBX4) and one patient had a variant of uncertain significance (VIP) suspected to contribute to their clinical phenotype, with VIP being a novel gene candidate. CONCLUSIONS: Trio exomes (6/36; 16.7%) had a better diagnostic rate than gene panel (1/36; 2.8%), due to the ability to consider a broader range of underlying conditions. However, the aetiology of chILD in most cases remained undetermined, likely reflecting the interplay between low penetrant genetic and environmental factors.

Protocol for establishing a core outcome set for evaluation in studies of pulmonary exacerbations in people with cystic fibrosis.

INTRODUCTION: Pulmonary exacerbations are associated with increased morbidity and mortality in people with cystic fibrosis (CF). There is no consensus about which outcomes should be evaluated in studies of pulmonary exacerbations or how these outcomes should be measured. Outcomes of importance to people with lived experience of the disease are frequently omitted or inconsistently reported in studies, which limits the value of such studies for informing practice and policy. To better standardise outcome reporting and measurement, we aim to develop a core outcome set for studies of pulmonary exacerbations in people with CF (COS-PEX) and consensus recommendations for measurement of core outcomes. METHODS AND ANALYSIS: Preliminary work for development of COS-PEX has been reported, including (1) systematic reviews of outcomes and methods for measurement reported in existing studies of pulmonary exacerbations; (2) workshops with people affected by CF within Australia; and (3) a Bayesian knowledge expert elicitation workshop with health professionals to ascertain outcomes of importance. Here we describe a protocol for the additional stages required for COS-PEX development and consensus methods for measurement of core outcomes. These include (1) an international two-round online Delphi survey and (2) consensus workshops to review and endorse the proposed COS-PEX and to agree with methods for measurement. ETHICS AND DISSEMINATION: National mutual ethics scheme approval has been provided by the Child and Adolescent Health Service Human Research Ethics Committee (RGS 4926). Results will be disseminated via consumer and research networks and peer-reviewed publications. This study is registered with the Core Outcome Measures in Effectiveness Trials database.

Prevalence of chronic respiratory diseases in Aboriginal children: A whole population study.

BACKGROUND: The burden of bronchiectasis is disproportionately high in Aboriginal adults, with early mortality. Bronchiectasis precursors, that is, protracted bacterial bronchitis (PBB) and chronic suppurative lung disease (CSLD), often commence in early childhood. We previously reported a 10% prevalence of PBB in Aboriginal children aged 0 to 7 years, however there are no data on prevalence of chronic lung diseases in older children. Our study aimed to determine the prevalence of PBB, CSLD, bronchiectasis, and asthma in Aboriginal children living in four communities. METHODS: A whole-population cross-sectional community co-designed study of Aboriginal children aged <18-years in four remote communities in Western Australia across two-time points, a month apart. Children were assessed by pediatric respiratory clinicians with spirometry undertaken (when possible) between March-September 2021. Children with respiratory symptoms were followed up via medical record audit from either the local medical clinic or via a respiratory specialist clinic through to March 2022 to establish a final diagnosis. FINDINGS: We recruited 392 (91.6%) of those in the selected communities; median age = 8.4 years (interquartile range [IQR] 5.1-11.5). Seventy children (17.9%) had a chronic respiratory pathology or abnormal spirometry results. PBB was confirmed in 30 (7.7%), CSLD = 13 (3.3%), bronchiectasis = 5 (1.3%) and asthma = 17 (4.3%). The prevalence of chronic wet cough significantly increased with increasing age. INTERPRETATION: The prevalence of PBB, CSLD and bronchiectasis is high in Aboriginal children and chronic wet cough increases with age. This study highlights the high disease burden in Aboriginal children and the urgent need for strategies to address these conditions.

Lung abscess: 14 years of experience in a tertiary paediatric hospital.

BACKGROUND: Lung abscess is a rare condition in paediatrics with a paucity of literature. Intravenous antibiotics is the main therapy; however interventional radiological approaches have led to the use of percutaneous drainage. Surgery is reserved for the management of complications. The aim of this study was to describe lung abscess in a cohort of paediatric patients' and determine associations between factors at presentation and outcomes. METHODS: A 14-year retrospective cohort study was conducted including all children who presented to a tertiary paediatric hospital in Western Australia with lung abscess. Clinical characteristics, laboratory and radiologic findings, management options and clinical outcomes were examined. RESULTS: Sixty-eight patients (median age 3.6 (0.08-17.6) years; 44.1% female) were identified to have a lung abscess, with 81% being primary lung abscess. Staphylococcus aureus (including MRSA) and Streptococcus pneumoniae were the most common organisms identified, with S. aureus being most common in Aboriginal patients (80%). A total of 25 antibiotics were prescribed on initiation of treatment in over 20 combinations. 44.9% of patients had complications and hospitalization was prolonged. Patients with S. aureus had longer hospitalization (20.5 days (3-67) than those without (median 13 days (3-52), p = 0.04). There were no associations between factors at presentation and subsequent outcomes. Factors at presentation were not associated with outcomes. CONCLUSION: There is unwarranted variation in management of paediatric lung abscess and high complication rates. There is a need for collaboration and clinical practice guidelines to standardize care for lung abscess in children.

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.

Inferring gene expression from cell-free DNA fragmentation profiles.

Profiling of circulating tumor DNA (ctDNA) in the bloodstream shows promise for noninvasive cancer detection. Chromatin fragmentation features have previously been explored to infer gene expression profiles from cell-free DNA (cfDNA), but current fragmentomic methods require high concentrations of tumor-derived DNA and provide limited resolution. Here we describe promoter fragmentation entropy as an epigenomic cfDNA feature that predicts RNA expression levels at individual genes. We developed 'epigenetic expression inference from cell-free DNA-sequencing' (EPIC-seq), a method that uses targeted sequencing of promoters of genes of interest. Profiling 329 blood samples from 201 patients with cancer and 87 healthy adults, we demonstrate classification of subtypes of lung carcinoma and diffuse large B cell lymphoma. Applying EPIC-seq to serial blood samples from patients treated with PD-(L)1 immune-checkpoint inhibitors, we show that gene expression profiles inferred by EPIC-seq are correlated with clinical response. Our results indicate that EPIC-seq could enable noninvasive, high-throughput tissue-of-origin characterization with diagnostic, prognostic and therapeutic potential.