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BACKGROUND: Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection. METHODS: This cohort study was done in emergency departments and intensive care units of four hospitals in Queensland, Australia, and recruited children aged 1 month to 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing of blood was performed with Illumina NovaSeq (San Diego, CA, USA). Samples with completed phenotyping, monitoring, and RNA extraction by March 31, 2020, were included in the discovery cohort; samples collected or completed thereafter and by Oct 27, 2021, constituted the Rapid Paediatric Infection Diagnosis in Sepsis (RAPIDS) internal validation cohort. An external validation cohort was assembled from RNA sequencing gene expression count data from the observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which recruited children with severe infection in nine European countries between 2012 and 2016. Feature selection approaches were applied to derive novel gene signatures for disease class (bacterial vs viral infection) and disease severity (presence vs absence of organ dysfunction 24 h post-sampling). The primary endpoint was the presence of organ dysfunction 24 h after blood sampling in the presence of confirmed bacterial versus viral infection. Gene signature performance is reported as area under the receiver operating characteristic curves (AUCs) and 95% CI. FINDINGS: Between Sept 25, 2017, and Oct 27, 2021, 907 patients were enrolled. Blood samples from 595 patients were included in the discovery cohort, and samples from 312 children were included in the RAPIDS validation cohort. We derived a ten-gene disease

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.

BACKGROUND: Following evidence from randomized controlled trials, patients with bronchiectasis unrelated to cystic fibrosis receive long-term azithromycin to reduce acute respiratory exacerbations. However, the period when azithromycin is effective and which patients are likely to most benefit remain unknown. RESEARCH QUESTIONS: (i) What is the period after its commencement when azithromycin is most effective? and (ii) Which factors may modify azithromycin effects? STUDY DESIGN AND METHODS: A secondary analysis was conducted of our previous randomized controlled trial involving 89 indigenous children with bronchiectasis unrelated to cystic fibrosis. Semi-parametric Poisson regression identified the azithromycin efficacy period. Multivariable Poisson regression identified factors that modify azithromycin effect. RESULTS: Azithromycin was associated with fewer exacerbations per child-week during weeks 4 through 96, with the most effective period observed between weeks 17 and 62. Eleven factors were associated with different azithromycin effects; four were significant at the P < .05 level. Compared with their counterparts, higher reduction in exacerbations was observed in children with nasopharyngeal carriage of bacterial pathogens (incidence rate ratio [IRR] = 0.81 [95% CI, 0.57-1.14] vs 0.29 [0.20-0.44]; P < .001); New Zealand children (IRR = 0.73 [0.51-1.03] vs 0.39 [0.28-0.55]; P = .012); and those with higher weight-for-height z scores (interaction IRR = 0.82 [0.67-0.99]; P = .044). Compared with their counterparts, lower reduction was observed in those born preterm (IRR = 0.41 [0.30-0.55] vs 0.74 [0.49-1.10]; P = .012). INTERPRETATION: Regular azithromycin is best used for at least 17 weeks and up to 62 weeks, as these periods provide maximum benefit for indigenous children with bronchiectasis unrelated to cystic fibrosis. Several factors modified azithromycin benefits; however, these traits need confirmation in larger studies before being adopted into clinical p

A new variant of Streptococcus pyogenes serotype M1 (designated 'M1UK') has been reported in the United Kingdom, linked with seasonal scarlet fever surges, marked increase in invasive infections, and exhibiting enhanced expression of the superantigen SpeA. The progenitor S. pyogenes 'M1global' and M1UK clones can be differentiated by 27 SNPs and 4 indels, yet the mechanism for speA upregulation is unknown. Here we investigate the previously unappreciated expansion of M1UK in Australia, now isolated from the majority of serious infections caused by serotype M1 S. pyogenes. M1UK sub-lineages circulating in Australia also contain a novel toxin repertoire associated with epidemic scarlet fever causing S. pyogenes in Asia. A single SNP in the 5' transcriptional leader sequence of the transfer-messenger RNA gene ssrA drives enhanced SpeA superantigen expression as a result of ssrA terminator read-through in the M1UK lineage. This represents a previously unappreciated mechanism of toxin expression and urges enhanced international surveillance.

A new variant of Streptococcus pyogenes serotype M1 (designated 'M1UK') has been reported in the United Kingdom, linked with seasonal scarlet fever surges, marked increase in invasive infections, and exhibiting enhanced expression of the superantigen SpeA. The progenitor S. pyogenes 'M1global' and M1UK clones can be differentiated by 27 SNPs and 4 indels, yet the mechanism for speA upregulation is unknown. Here we investigate the previously unappreciated expansion of M1UK in Australia, now isolated from the majority of serious infections caused by serotype M1 S. pyogenes. M1UK sub-lineages circulating in Australia also contain a novel toxin repertoire associated with epidemic scarlet fever causing S. pyogenes in Asia. A single SNP in the 5' transcriptional leader sequence of the transfer-messenger RNA gene ssrA drives enhanced SpeA superantigen expression as a result of ssrA terminator read-through in the M1UK lineage. This represents a previously unappreciated mechanism of toxin expression and urges enhanced international surveillance.

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

Introduction Mobile phones are used the world over, including in healthcare settings. This study aimed to investigate the viable microbial colonisation of mobile phones used by healthcare personnel. Methods Swabs collected on the same day from 30 mobile phones belonging to healthcare workers from three separate paediatric wards of an Australian hospital were cultured on five types of agar plate, then colonies from each phone were pooled, extracted and sequenced by shotgun metagenomics. Questionnaires completed by staff whose phones were sampled assisted in the analysis and interpretation of results. Results and discussion All phones sampled cultured viable bacteria. Overall, 399 bacterial operational taxonomic units were identified from 30 phones, with 1432 cumulative hits. Among these were 58 recognised human pathogenic and commensal bacteria (37 Gram-negative, 21 Gram-positive). The total number of virulence factor genes detected was 347, with 1258 cumulative hits. Antibiotic resistance genes (ARGs) were detected on all sampled phones and overall, 133 ARGs were detected with 520 cumulative hits. The most important classes of ARGs detected encoded resistance to beta-lactam, aminoglycoside and macrolide antibiotics and efflux pump mediated resistance mechanisms. Conclusion Mobile phones carry viable bacterial pathogens and may act as fomites by contaminating the hands of their users and indirectly providing a transmission pathway for hospital-acquired infections and dissemination of antibiotic resistance. Further research is needed, but meanwhile adding touching mobile phones to the five moments of hand hygiene is a simple infection control strategy worth considering in hospital and community settings. Additionally, the implementation of practical and effective guidelines to decontaminate mobile phone devices would likely be beneficial to the hospital population and community at large.

Background: While there have been studies in adults reporting discordant empiric antibiotic treatment associated with poor outcomes, this area is relatively unexplored in children and neonates despite evidence of increasing resistance to recommended first-line treatment regimens. Method(s): Patient characteristics, antibiotic treatment, microbiology, and 30-day all-cause outcome from children <18 years with blood-culture-confirmed bacterial bloodstream infections (BSI) were collected anonymously using REDCapTM through the Global Antibiotic Prescribing and Resistance in Neonates and Children network from February 2016 to February 2017. Concordance of early empiric antibiotic treatment was determined using European Committee on Antimicrobial Susceptibility Testing interpretive guidelines. The relationship between concordance of empiric regimen and 30-day mortality was investigated using multivariable regression. Result(s): Four hundred fifty-two children with blood-culture-positive BSI receiving early empiric antibiotics were reported by 25 hospitals in 19 countries. Sixty percent (273/452) were under the age of 2 years. S. aureus, E. coli, and Klebsiella spp. were the most common isolates, and there were 158 unique empiric regimens prescribed. Fifteen percent (69/452) of patients received a discordant regimen, and 7.7% (35/452) died. Six percent (23/383) of patients with concordant regimen died compared with 17.4% (12/69) of patients with discordant regimen. Adjusting for age, sex, presence of comorbidity, unit type, hospital-acquired infections, and Gram stain, the odds of 30-day mortality were 2.9 (95% confidence interval: 1.2-7.0; P = 0.015) for patients receiving discordant early empiric antibiotics. Conclusion(s): Odds of mortality in confirmed pediatric BSI are nearly 3-fold higher for patients receiving a discordant early empiric antibiotic regimen. The impact of improved concordance of early empiric treatment on mortality, particularly in critically ill patie

Little is known about early predictors of later cystic fibrosis (CF) structural lung disease. This study examined early predictors of progressive structural lung abnormalities in children who completed the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial at age 5-years and participated in an observational follow-up study (CF-FAB). Eight Australian and New Zealand CF centres participated in CF-FAB and provided follow-up chest computed-tomography (CT) scans for children who had completed the ACFBAL study with baseline scans at age 5-years. CT scans were annotated using PRAGMA-CF scoring. Ordinal regression analysis and linear regression were used to investigate associations between PRAGMA-CF (Perth-Rotterdam Annotated Grid Morphometric Analysis for CF) outcomes at follow-up and variables measured during the ACFBAL study. 99 out of 157 ACFBAL children (mean+/-SD age 13+/-1.5 years) participated in the CF-FAB study. The probability of bronchiectasis at follow-up increased with airway disease severity on the baseline CT scan. In multiple regression (retaining factors at p<0.05) the extent of bronchiectasis at follow-up was associated with baseline atelectasis (OR 7.2, 95% CI 2.4-22; p 0.001), bronchoalveolar lavage (BAL) log2 interleukin (IL)-8 (OR 1.2, 95% CI 1.05-1.5; p=0.010) and body mass index z-score (OR 0.49, 95% CI 0.24-1.00; p=0.05) at age 5 years. Percentage trapped air at follow-up was associated with BAL log2 IL-8 (coefficient 1.3, 95% CI 0.57-2.1; p<0.001) at age 5 years. The extent of airway disease, atelectasis, airway inflammation and poor nutritional status in early childhood are risk factors for progressive structural lung disease in adolescence.Copyright © ERS 2020

Little is known about early predictors of later cystic fibrosis (CF) structural lung disease. This study examined early predictors of progressive structural lung abnormalities in children who completed the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial at age 5-years and participated in an observational follow-up study (CF-FAB).Eight Australian and New Zealand CF centres participated in CF-FAB and provided follow-up chest computed-tomography (CT) scans for children who had completed the ACFBAL study with baseline scans at age 5-years. CT scans were annotated using PRAGMA-CF scoring. Ordinal regression analysis and linear regression were used to investigate associations between PRAGMA-CF (Perth-Rotterdam Annotated Grid Morphometric Analysis for CF) outcomes at follow-up and variables measured during the ACFBAL study.99 out of 157 ACFBAL children (mean±sd age 13±1.5 years) participated in the CF-FAB study. The probability of bronchiectasis at follow-up increased with airway disease severity on the baseline CT scan. In multiple regression (retaining factors at p<0.05) the extent of bronchiectasis at follow-up was associated with baseline atelectasis (OR 7.2, 95% CI 2.4-22; p≤ 0.001), bronchoalveolar lavage (BAL) log2 interleukin (IL)-8 (OR 1.2, 95% CI 1.05-1.5; p=0.010) and body mass index z-score (OR 0.49, 95% CI 0.24-1.00; p=0.05) at age 5 years. Percentage trapped air at follow-up was associated with BAL log2 IL-8 (coefficient 1.3, 95% CI 0.57-2.1; p<0.001) at age 5 years.The extent of airway disease, atelectasis, airway inflammation and poor nutritional status in early childhood are risk factors for progressive structural lung disease in adolescence.

Background: The inter-jurisdictional National Mutual Acceptance (NMA) scheme for Human Research Ethics Committee (HREC) approvals of human research is designed to reduce the reported delays and costs of ethical review. Introduction of the NMA set forth an uncoupling of the ethics and governance review processes, permitting a single ethical review for multiple sites, while continuing separate governance review for each centre covering financial and operational aspects of the research project. Aim(s): To compare the time required to gain ethics and governance approvals in Australia for a non-interventional investigator-led study from December 2015 to approval times for an earlier pre-NMA study utilising a similar study design and study sites and evaluate the effect that the NMA has had on total approval time for non-interventional multi-centre projects. Method(s): We recorded the time taken to obtain ethics and governance approval at 16 sites for our nationwide low-risk non-interventional study looking at the prevalence and aetiology of non-tuberculous mycobacterial infection in people with cystic fibrosis in Australia. Result(s): Applications were submitted to three hospitals and one university HREC to conduct our study at 16 hospital sites, HREC approval took from 16 to 79 days (median 28). Subsequent site-specific governance approval at 15 hospital sites took 23-225 days (median 83). The entire process of gaining ethical and governance approval to conduct the study at 16 sites took 24 months at an estimated cost of AU$56000 (US$ 42 000). Conclusion(s): Lengthy governance approval processes negate benefits gained from centralised ethics review under the NMA.Copyright © 2018 Royal Australasian College of Physicians

Background: Cystic fibrosis (CF) lung disease commences in infancy, and understanding the role of the microbiota in disease pathogenesis is critical. This study examined and compared the lower airway microbiota of infants with and without CF and its relationship to airway inflammation in the first months of life. Method(s): Infants newly-diagnosed with CF were recruited into a single-centre study in Melbourne, Australia from 1992 to 2001. Bronchoalveolar lavage was performed at study entry. Healthy infants undergoing bronchoscopy to investigate chronic stridor acted as controls. Quantitative microbiological culture was performed and inflammatory markers were measured contemporaneously. 16S ribosomal RNA gene analysis was performed on stored samples. Result(s): Thirteen bronchoalveolar samples from infants with CF and nine from control infants, collected at median ages of 1.8-months (25th-75th percentile 1.5 to 3.1-months) and 5-months (25th-75th percentile 2.9 to 8.2-months) respectively, provided 16S rRNA gene data. Bacterial biomass was positively associated with inflammation. Alpha diversity was reduced in infants with CF and between-group compositional differences were apparent. These differences were driven by increased Staphylococcus and decreased Fusobacterium and were most apparent in symptomatic infants with CF. Conclusion(s): In CF lung disease, differences in lower airway microbial community composition and structure are established by age 6-months.Copyright © 2018 European Cystic Fibrosis Society.

BACKGROUND: The inter-jurisdictional National Mutual Acceptance (NMA) scheme for Human Research Ethics Committee (HREC) approvals of human research is designed to reduce the reported delays and costs of ethical review. Introduction of the NMA set forth an uncoupling of the ethics and governance review processes, permitting a single ethical review for multiple sites, while continuing separate governance review for each centre covering financial and operational aspects of the research project. AIM: To compare the time required to gain ethics and governance approvals in Australia for a non-interventional investigator-led study from December 2015 to approval times for an earlier pre-NMA study utilising a similar study design and study sites and evaluate the effect that the NMA has had on total approval time for non-interventional multi-centre projects. METHODS: We recorded the time taken to obtain ethics and governance approval at 16 sites for our nationwide low-risk non-interventional study looking at the prevalence and aetiology of non-tuberculous mycobacterial infection in people with cystic fibrosis in Australia. RESULTS: Applications were submitted to three hospitals and one university HREC to conduct our study at 16 hospital sites, HREC approval took from 16 to 79 days (median 28). Subsequent site-specific governance approval at 15 hospital sites took 23-225 days (median 83). The entire process of gaining ethical and governance approval to conduct the study at 16 sites took 24 months at an estimated cost of AU$56000 (US$ 42 000). CONCLUSION: Lengthy governance approval processes negate benefits gained from centralised ethics review under the NMA.

Background: Most respiratory bacterial carriage studies in children are based on cross-sectional samples or longitudinal studies with infrequent sampling points. The prospective Observational Research in Childhood Infectious Diseases birth cohort study intensively evaluated the community-based epidemiology of respiratory viruses and bacteria during the first 2-years of life. Here we report the bacteriologic findings. Methods: Pregnant women in Brisbane, Australia were recruited between September 2010 and October 2012, and their healthy newborn children were followed for the first 2-years of life. Parents kept a daily symptom diary for the study child, collected a weekly anterior nose swab and completed an illness burden diary when their child met pre-defined illness criteria. Specimens were tested for respiratory bacteria by real-time polymerase chain reaction (PCR) assays and those containing human genomic DNA, deemed as high-quality, were analyzed. Results: Altogether 8100 high-quality nasal swab specimens from 158 enrolled children were analyzed. Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae were detected in 42.4%, 38.9%, and 14.8% of these samples, respectively. Concomitant detection of bacteria was common. In contrast, Bordetella pertussis, B. parapertussis, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Simkania negevensis were rarely identified. The prevalence of the three major bacteria was higher with increasing age and in the winter and spring months. Siblings and childcare attendance were the other risk factors identified. Conclusions: We confirmed the feasibility of frequent nasal swabbing by parents for studying bacterial colonization. PCR detected the major respiratory tract bacteria with expected high frequencies, but atypical bacteria were found rarely in this cohort.