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Background: Despite improvements in general health and life expectancy in people with cystic fibrosis (CF), lung function decline continues unabated during adolescence and early adult life. Methods: We examined factors present at age 5-years that predicted lung function decline from childhood to adolescence in a longitudinal study of Australasian children with CF followed from 1999 to 2017. Results: Lung function trajectories were calculated for 119 children with CF from childhood (median 5.0 [25%-75%=5.0–5.1]) years) to early adolescence (median 12.5 [25%-75%=11.4–13.8] years). Lung function fell progressively, with mean (standard deviation) annual change -0.105 (0.049) for forced vital capacity (FVC) Z-score (p1) Z-score (p1/FVC% (p1/FVC p = 0.001, FEF25–75 p = 0.01) and bronchoalveolar lavage neutrophil elastase activity (FEV1/FVC% p = 0.001, FEV1 p = 0.05, FEF25–75 p = 0.02). No examined factor predicted a decline in the FVC Z-score. Conclusions: Action in the first 5-years of life to prevent and/or treat respiratory exacerbations and counteract neutrophilic inflammation in the lower airways may reduce lung function decline in children with CF, and these should be targets of future research.

AIM To identify interventions that reduce hospitalisations and improve related outcomes in children at risk of asthma hospital admissions. METHODS Medline, Embase, Pubmed and Cochrane Library search from January 2002 to April 2020. INCLUSION CRITERIA randomised controlled trials of any intervention for children with asthma who are at risk of hospitalisations. OUTCOMES hospitalisation (primary outcome), rescue oral corticosteroid use, school absences, quality of life and cost-effectiveness. RESULTS Twelve randomised controlled trials were conducted with 2719 participants. Due to heterogeneity of interventions and reporting of outcomes, a meta-analysis was not conducted. Multi-modal interventions comprising caregiver education, reduction of home environmental allergens and regular follow-up reduced hospitalisations, rescue corticosteroid use and improved quality of life. Cost-effectiveness was not reported. Three studies scored an overall low risk of bias, and nine had some concerns. CONCLUSION Multi-modal interventions can be effective in reducing hospitalisations, rescue oral corticosteroid use and quality of life but cost-effectiveness is unknown.

We read with great interest the recent publication by Steinfort et al. [1] outlining the profound reduction in influenza infections in Australia as a result of social distancing during the COVID-19 pandemic. Similar dramatic effects of social distancing on paediatric hospital activity have been reported, with reduced hospital admissions, presentations for respiratory conditions, and detection of other viruses [2–6]. However, the impact of the pandemic on bacterial respiratory infections has not been well characterised. The Australian state of Victoria (population 6.7 million) has experienced a prolonged period of social restrictions (“lockdown”) since March 2020. This period spanned the Southern Hemisphere Autumn to Spring, the usual peak period for bacterial respiratory infections., Social distancing measures instituted due to #SARSCoV2 have dramatically reduced paediatric thoracic empyema cases in Australia

Background: Cashew is a common cause of tree nut allergy in children. To date there have been few studies of diagnostic tests for cashew allergy, and positive predictive values (PPVs) for cashew as well as other tree nuts are largely extrapolated from studies of peanut allergy. How relevant these cutoffs are for cashew has not been formally explored. Objective: We aimed to establish skin prick test (SPT) wheal sizes that correlated to 95% PPV for a positive food challenge for cashew. Methods: We included all cashew oral food challenges (OFCs) conducted as part of the HealthNuts (n = 108; age, 4-6 years) and SchoolNuts (n = 37; age, 10-14 years) studies, both recruited from the community (population cohort). A second cohort of all cashew OFCs conducted at the Royal Children's Hospital (RCH) allergy center (n = 343) (2011-2016) and a private allergy clinic based at RCH (n = 43) was included via electronic medical record review (clinic cohort). The 95% PPV for cashew SPT was calculated for both cohorts. Results: Among the population cohort (n = 145), 62% of cashew OFCs were positive compared with 20% of the clinic cohort (n = 386). The SPT cutoff for 95% PPV derived from the population cohort was 10 mm (95% confidence interval [CI], 7.5-12.0). For the clinic cohort, the 95% PPV was 14 mm (95% CI, 9.5-unknown). An SPT wheal size of 8 mm had a PPV of 89% (95% CI, 79-95) in the population cohort and 62% (95% CI, 45-78) in the clinic cohort. Conclusion: A higher SPT wheal size may be more appropriate than the commonly used 8 mm cutoff to guide clinical decisions around when to perform OFC for cashew.

Brown-Vialetto-van Laere syndrome is characterized by a progressive sensorimotor neuropathy, optic atrophy, hearing loss, bulbar dysfunction, and respiratory insufficiency. Mutations in SLC52A2 and SLC52A3, encoding riboflavin transporters RFVT2 and RFVT3, respectively, are the genetic basis of this disorder, often referred to as riboflavin transporter deficiency types 2 and 3, respectively. We present cases of both types of riboflavin transporter deficiency, highlighting the distinguishing clinical features of a rapidly progressive motor or sensorimotor axonal neuropathy, optic atrophy, sensorineural hearing loss, and bulbar dysfunction. One child presented with isolated central apnea and hypoventilation, not previously described in genetically confirmed Brown-Vialetto-van Laere, later complicated by diaphragmatic paralysis secondary to phrenic nerve palsy. Magnetic resonance imaging showed T2 hyperintensity in the dorsal spinal cord in 2 children, as well as previously unreported cervical nerve root enlargement and cauda equina ventral nerve root enhancement in 1 child. Novel homozygous mutations were identified in each gene-a NM_024531.4(SLC52A2):c.505C > T, NP_078807.1(SLC52A2):p.(Arg169Cys) variant in SLC52A2 and NM_033409.3(SLC52A3):c.1316G > A, NP_212134.3(SLC52A3):p.(Gly439Asp) variant in SLC52A3. Both treated children showed improvement on high-dose riboflavin supplementation, highlighting the importance of early recognition of this treatable clinical entity.

Background: Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed. Objective: We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes. Methods: We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both . cis- and . trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations. Results: We tested the association between asthma and 17,190 genes that were found to have . cis- and/or . trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, . LIMS1, . TINF2, and . SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: . B4GALT3, . USMG5, . P2RY13, and . P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs. Conclusion: We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs.

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 p2 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; pThe extent of airway disease, atelectasis, airway inflammation and poor nutritional status in early childhood are risk factors for progressive structural lung disease in adolescence.

Rationale: Historical studies suggest that airway infection in cystic fibrosis initiates with Staphylococcus aureus and Haemophilus influenzae, with later emergence of Pseudomonas aeruginosa. Asper...

Background The evolution of airway obstruction into late adolescence of extremely preterm (gestational age Objective To compare changes in spirometry from 8 to 18 years of age of a geographical cohort of preterm survivors with normal birth weight controls, and to determine higher risk groups within the preterm cohort. Methods Of 297 extremely preterm/low-birthweight survivors born in 1991–1992 in the state of Victoria, Australia, 81% and 70% had spirometry at 8 and 18 years of age, respectively. Corresponding rates among 260 normal birth weight controls were 80% and 58%, respectively. Data were analysed using linear mixed models. Results The preterm group had substantial impairments in airflow at both ages compared with controls (eg, mean differences in z-score for FEV 1 ; 8 years −1.02, 95% CI −1.21 to −0.82; 18 years −0.92, 95% CI −1.14 to −0.71). The preterm group had a greater increase in small airway obstruction between 8 and 18 years compared with controls. Within the preterm group, those who had bronchopulmonary dysplasia in the newborn period and those who were smokers at 18 years had airway obstruction that increased over time compared with those who did not. Conclusions Preterm survivors born in the surfactant era had significant impairments in airflow through childhood into late adolescence that increased over time compared with controls. At-risk preterm participants include those who had bronchopulmonary dysplasia, and smokers at 18 years.

Background There are no published data on the critical review of chest X-ray (CXR) findings of children in the context of community-based contact screening. Objectives To describe the quality, findings and inter-observer agreement of CXRs in child TB contacts in Indonesia. Methods We performed antero-posterior (AP) and lateral CXR in children who had had close contact with a pulmonary TB case. The CXRs were interpreted independently by four reviewers. Results A total of 530 CXRs of 265 children were reviewed. Most (63%) of the children were asymptomatic at the time of CXR. Only 60% of the CXRs were reported as moderate to good quality by all reviewers, and inter-observer agreement on quality was slight to moderate (weighted κ = 0.16-0.35) for AP view. The majority of the CXRs were reported as normal (range 65-77%), with fair to moderate inter-observer agreement (κ = 0.25-0.46). Hilar lymphadenopathy (6-16%) was the most common CXR abnormality reported with poor inter-observer agreement (κ = -0.03 to 0.25). Conclusion The CXRs of child TB contacts investigated in the community were characterised by low quality, low agreement and low yield. Our findings support guidelines that CXR is not routinely indicated in asymptomatic child TB contacts in this setting.

The postnatal management of asymptomatic antenatally detected congenital lung malformations (CLM) has been controversial. The aim of this project is to report the clinical outcome of a non-operative approach to management of CLMs detected antenatally. The medical records of all children with CLM detected antenatally, born between 1999 and 2014 and referred to the Royal Children’s Hospital, Melbourne were reviewed. 113 patients were identified with a median follow up period of 7.9 years. Chest x-rays performed in the first year were available for review. No abnormality was detected in 31 overall and only 2 of those who ultimately had resection. In the neonatal period, 2 infants died prior to surgery (hydrops/prematurity) and 6 had resection of which 1, who had alveolar capillary dysplasia, died. Beyond infancy, 17 became symptomatic of whom 13 had resection (mass effect 3, infection in CLM 10) and 5 were managed conservatively. 88 remained asymptomatic of whom 11 had elective resection (parent request 2, recurrent cough, not related to CLM 2, mass effect 3, not specified 4) and 77/113 (68%) managed conservatively. There has been 1 death in this group unrelated to CLM. No malignancies were identified. In conclusion, a non-operative approach provides a safe and effective strategy for the management of antenatally detected CLMs with excellent medium to long term clinical outcome.

The treatment of Mycobacterium abscessus complex (MABSC) pulmonary infections is an emerging challenge in patients with cystic fibrosis (CF). Multidrug therapy for prolonged durations is required and carries the significant burden of drug-related toxicity, cost and selective pressure for multiresistant bacteria. International guidelines acknowledge that clinical and in vitro data to support treatment regimens are limited, particularly in children. As part of a collaboration between the infectious diseases and respiratory units at our institution, we have developed a modified treatment guideline that aims to balance the aims of MABSC eradication and slowing disease progression with minimising drug toxicity and resistance. The outcomes of this treatment approach will be monitored and reported. In this manuscript, we discuss the available evidence for treatment choices and present our treatment guideline for paediatric patients with CF and MABSC infection.

It is hypothesised that the impaired skin barrier in atopic dermatitis (AD) allows the immune system to be exposed to environmental allergens, resulting in sensitisation and allergic disease[1]. Two small trials recently found that routine use of emollients reduced the incidence of AD during the active treatment period by approximately half [2, 3]. It remains unknown if prophylactic use of emollients can prevent the development of AD beyond the treatment period (as opposed to simply delay its onset) or if this reduction in AD leads to a reduced risk of allergic sensitisation. This article is protected by copyright. All rights reserved.

BACKGROUND Chronic cough is associated with poor quality of life and may signify a serious underlying disease. Differentiating nonspecific cough (when watchful waiting can be safely undertaken) from specific cough (treatment and further investigations are beneficial) would be clinically useful. In 326 children, we aimed to (1) determine how well cough pointers (used in guidelines) differentiate specific from nonspecific cough and (2) describe the clinical profile of children whose cough resolved without medications (spontaneous resolution). METHODS A dataset from a multicenter study involving children newly referred for chronic cough (median duration, 3-4 months) was used to determine the sensitivity, specificity, predictive values, and likelihood ratios (LRs) of cough pointers (symptoms, signs, and simple investigations [chest radiography, spirometry]) recommended in guidelines. RESULTS The pretest probability of specific cough was 88%. The absence of false-positive results meant that most pointers had strongly positive LRs. The most sensitive pointer (wet cough) had a positive LR of 26.2 (95% CI, 3.8-181.5). Although the absence of other individual pointers did not change the pretest probability much (negative LR close to 1), the absence of all pointers had a strongly negative LR of 0 (95% CI, 0-0.03). Children in the resolved spontaneously group were significantly more likely to be older, to be non-Indigenous, and to have a dry cough and a normal chest radiograph. CONCLUSIONS Children with chronic dry cough without any cough pointers can be safely managed using the watchful waiting approach. The high pretest probability and high positive LRs of cough pointers support the use of individual cough pointers to identify high risk of specific cough in pediatric chronic cough guidelines. TRIAL REGISTRY Australian New Zealand Clinical Trials Registry; No.: 12607000526471; URL:www.anzctr.org.au

Chronic respiratory morbidity is a common complication of premature birth, generally defined by the presence of bronchopulmonary dysplasia, both clinically and in trials of respiratory therapies. However, recent data have highlighted that bronchopulmonary dysplasia does not correlate with chronic respiratory morbidity in older children born preterm. Longitudinally evaluating pulmonary morbidity from early life through to childhood provides a more rational method of defining the continuum of chronic respiratory morbidity of prematurity, and offers new insights into the efficacy of neonatal respiratory interventions. The changing nature of preterm lung disease suggests that a multimodal approach using dynamic lung function assessment will be needed to assess the efficacy of a neonatal respiratory therapy and predict the long-term respiratory consequences of premature birth. Our aim is to review the literature regarding the long-term respiratory outcomes of neonatal respiratory strategies, the difficulties of assessing dynamic lung function in infants, and potential new solutions.

Background The risk of developing asthma in those with early food allergy is unknown, particularly when early life food allergy has resolved. Objective To understand whether challenge-proven food allergy in infancy increases the risk of asthma at age 4 years, using data from a population-based cohort. Methods A total of 5,276 12-month-old infants were recruited using a population-based sampling frame. Infants underwent skin prick test to egg, peanut, and sesame and those with a detectable skin prick test result had oral food challenges. At age 4 years, food challenges were repeated to determine persistence or resolution of food allergy. The association between food allergy and doctor-diagnosed asthma was examined using binomial regression in 2,789 participants. Results Children with food allergy at age 1 year had an increased risk of asthma (1 food allergy: relative risk [RR], 1.69; 95% CI, 1.29-2.21; 2 or more food allergies: RR, 2.76; 95% CI, 1.94-3.92). The risk of asthma was highest in children with food allergy and coexistent eczema in infancy (RR, 2.87; 95% CI, 2.22-3.70). Transient food allergy and persistent food allergy were both associated with an increased risk of asthma (transient egg allergy: RR, 1.92; 95% CI, 1.46-2.51; persistent egg allergy: RR, 2.60; 95% CI, 1.76-3.85). Conclusions Asthma at age 4 years is twice as common in those with challenge-proven food allergy at age 1 year, irrespective of whether the food allergy subsequently resolves. Children with 2 or more food allergies and those with coexistent eczema were almost 3 times as likely to develop asthma compared with those with no food allergies.

Research to further improve outcomes for people with CF is dependent upon well characterised, archived and accessible clinical specimens. The recent article by Beekman et al. published in Journal of Cystic Fibrosis summarised a scientific meeting at the 13th ECFS Basic Science Conference. This meeting discussed how well-annotated, clinical biobanks for CF could be established in Europe to meet the needs of therapeutic development. The Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) has conducted biobanking of CF research and clinical specimens since the late 1990s and is custodian of the most comprehensive paediatric CF biobank in the world that focuses on the first years of life. This short communication will describe the approach undertaken by AREST CF in establishing a clinical specimen biobank.

BACKGROUND: Child tuberculosis contact screening and management can enhance case finding and prevent tuberculosis disease. It is universally recommended but rarely implemented in tuberculosis-endemic settings. The World Health Organization (WHO)-recommended symptom-based screening approach could improve implementation but has not been prospectively evaluated. METHODS: We conducted a cohort study of children who were close contacts of pulmonary tuberculosis patients in Indonesia from August 2010 to December 2012. We performed clinical assessment, tuberculin skin test, and chest radiography in all eligible children irrespective of symptoms at baseline. Mycobacterial culture and Xpert MTB/RIF assay were performed on sputum from children with persistent symptoms of suspected tuberculosis. Children were managed according to WHO guidelines and were prospectively followed for 12 months. RESULTS: A total of 269 child contacts of 140 index cases were evaluated. At baseline, 21 (8%) children had tuberculosis diagnosed clinically; an additional 102 (38%) had evidence of infection without disease. Of children with any tuberculosis-related symptoms at baseline, 21% had tuberculosis diagnosed compared with none of the asymptomatic children (P < .001). After 12 months of follow-up, none of the 99 eligible young child contacts (

Summary Introduction The lung function outcome of cohorts of very low birth weight (VLBW; birth weight 2499 g), and in those who had bronchopulmonary dysplasia (BPD) compared with those without BPD. Materials and Methods Spirometry and lung volumes were measured according to standard guidelines when subjects were in their mid-20s; there were 47 survivors of birth weight 2499 g. Results were converted to z-scores. Results Both subgroups with birth weight

Background To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. Objective We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. Methods We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). Results At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10 −9 ) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10 −8 ). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP . Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10 −7 ) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10 −6 ). Conclusion By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

IntroductionThe skin is an important barrier against environmental allergens, but infants have relatively impaired skin barrier function. There is evidence that impaired skin barrier function increases the risk of allergic sensitisation, atopic dermatitis (AD) and food allergy. We hypothesise that regular prophylactic use of emollients, particularly those that are designed to improve skin barrier structure and function, will help prevent these conditions. With the aim of determining if application of a ceramide-dominant emollient two times per day reduces the risk of AD and food allergy, we have commenced a multicentre phase III, outcome assessor blinded, randomised controlled trial of this emollient applied from birth to 6 months.Methods and analysisInfants (n=760) with a family history of allergic disease will be recruited from maternity hospitals in Melbourne. The primary outcomes are as follows: the presence of AD, assessed using the UK Working Party criteria, and food allergy using food challenge, in the first 12 months of life as assessed by a blinded study outcome assessor. Secondary outcomes are as follows: food sensitisation (skin prick test), skin barrier function, AD severity, the presence of new onset AD after treatment cessation (between 6 and 12 months) and the presence of parent reported AD/eczema. Recruitment commenced in March 2018.Ethics and disseminationThe PEBBLES Study is approved by the Human Research Ethics Committees of the Royal Children’s Hospital (RCH) (#37090A) and the Mercy Hospital for Women (2018–008). Parents or guardians will provide written informed consent. Outcomes will be disseminated through peer-reviewed publications and presented at scientific conferences.Trial registration numbersACTRN12617001380381 andNCT03667651.

Background Longitudinal population-based data regarding tree nut allergy are limited. Objectives We sought to determine the population prevalence of tree nut allergy at age 6 years and explore the relationship between egg and peanut allergy at age 1 year and development of tree nut allergy at age 6 years. Methods A population-based sample of 5276 children was recruited at age 1 year and followed up at age 6 years. At age 1 year, allergies to egg and peanut were determined by means of oral food challenge, and parents reported their child's history of reaction to tree nuts. Challenge-confirmed tree nut allergy was assessed at age 6 years. Results At age 1 year, the prevalence of parent-reported tree nut allergy was 0.1% (95% CI, 0.04% to 0.2%). Only 18.5% of infants had consumed tree nuts in the first year of life. At age 6 years, challenge-confirmed tree nut allergy prevalence was 3.3% (95% CI, 2.8% to 4.0%), with cashew the most common (2.7%; 95% CI, 2.2% to 3.3%). Of children with peanut allergy only at age 1 year, 27% (95% CI, 16.1% to 39.7%) had tree nut allergy at age 6 years compared with 14% (95% CI, 10.4% to 17.9%) of those with egg allergy only and 37% (95% CI, 27.2% to 47.4%) of those with both peanut and egg allergy. Conclusions Tree nut allergy is uncommon in the first year of life, likely because of limited tree nut consumption. At age 6 years, tree nut allergy prevalence is similar to peanut allergy prevalence. More than a third of children with both peanut and egg allergy in infancy have tree nut allergy at age 6 years. Understanding how to prevent tree nut allergy should be an urgent priority for future research.

Summary Introduction Though baseline lung function as measured by spirometry in children with cystic fibrosis (CF) has improved, the annual rate of decline has not changed significantly during the critical period of adolescence. The aim of this study was to describe factors associated with longitudinal decline in lung function in a contemporary cohort of children with CF. Methods Best annual lung function data from children attending the CF service of the Royal Children's Hospital Melbourne were reviewed to determine rate of decline in FEV1 up until time of transfer to an adult center. Mixed models were used to determine the influence of age, sex, genotype, newborn screening, respiratory hospitalization, CF related diabetes mellitus (CFRD), pancreatic insufficiency, Pseudomonas aeruginosa (PsA) infection, and body mass index (BMI) on lung function decline. Results Longitudinal lung function data (range 5–20 years) were obtained for 98 patients with CF (55 male). Overall, the annual rate of decline in FEV1 % predicted for the entire cohort was 1.4% per annum though the greatest rate of FEV1 decline was seen during adolescence (2.6%). Increasing age, homozygous ΔF508 genotype, CFRD, mucoid PsA infection, pancreatic insufficiency and respiratory hospitalizations were all significant predictors of FEV1 decline. Conclusion FEV1 declines at its sharpest rate during adolescence even in the presence of newborn screening. Genotype, increasing age, CFRD, PsA infection, pancreatic insufficiency and a greater number of respiratory hospitalizations are all associated with an increased rate of lung function decline in Australian children and adolescents with cystic fibrosis. Pediatr Pulmonol. 2014; 49:873–877. © 2013 Wiley Periodicals, Inc.

OBJECTIVES The goals of this study were to: (1) determine if management according to a standardized clinical management pathway/algorithm (compared with usual treatment) improves clinical outcomes by 6 weeks; and (2) assess the reliability and validity of a standardized clinical management pathway for chronic cough in children. METHODS: A total of 272 children (mean ± SD age: 4.5 ± 3.7 years) were enrolled in a pragmatic, multicenter, randomized controlled trial in 5 Australian centers. Children were randomly allocated to 1 of 2 arms: (1) early review and use of cough algorithm (“early-arm”); or (2) usual care until review and use of cough algorithm (“delayed-arm”). The primary outcomes were proportion of children whose cough resolved and cough-specific quality of life scores at week 6. Secondary measures included cough duration postrandomization and the algorithm’s reliability, validity, and feasibility. RESULTS: Cough resolution (at week 6) was significantly more likely in the early-arm group compared with the delayed-arm group (absolute risk reduction: 24.7% [95% confidence interval: 13–35]). The difference between cough-specific quality of life scores at week 6 compared with baseline was significantly better in the early-arm group (mean difference between groups: 0.6 [95% confidence interval: 0.29–1.0]). Duration of cough postrandomization was significantly shorter in the early-arm group than in the delayed-arm group (P = .001). The cough algorithm was reliable (κ = 1 in key steps). Feasibility was demonstrated by the algorithm’s validity (93%–100%) and efficacy (99.6%). Eighty-five percent of children had etiologies easily diagnosed in primary care. CONCLUSIONS: Management of children with chronic cough, in accordance with a standardized algorithm, improves clinical outcomes irrespective of when it is implemented. Further testing of this standardized clinical algorithm in different settings is recommended.

With ABO blood group incompatibility (ABOi) between donor and recipient becoming a part of mainstream living-donor renal transplantation, the applicability of ABOi to other areas of transplantation is being reconsidered. Here we present a case of inadvertent ABOi lung retransplantation managed successfully with initial plasmapheresis, antithymocyte globulin and intravenous immunoglobulin; and subsequently with oral cyclophosphamide and sirolimus in addition to tacrolimus and prednisolone. Interestingly, in the setting of solid levels of tacrolimus and sirolimus, the patient developed a fatal thrombotic microangiopathy of uncertain origin subsequent to the cessation of cyclophosphamide at 9 years posttransplant. It is apparent that ABOi lung transplantation can result in surprisingly successful long-term outcomes. Low pretransplant antibody titers likely aid this and, in pediatric neonatal or infant cases, this may not be uncommon. We must proceed cautiously as there are significant risks. Understanding the monitoring, prevention and treatment of lung transplant antibody-mediated rejection, while avoiding the long-term complications of overimmunosuppression, will be the keys to the success of future cases.

Background Severe tracheal stenosis is a rare life-threatening condition that often requires early surgical intervention. The management of this anomaly has been associated with significant mortality and morbidity. We describe our experience with repair of this condition. Methods From 1986 to 2011, 20 patients underwent repair of tracheal stenosis at the Royal Children's Hospital (median age 4.9 months) and were retrospectively reviewed. Results Tracheal repair techniques used were as follows: patch tracheoplasty (n = 8; 40%, 8 out of 20), slide tracheoplasty (n = 7; 35%, 7 out of 20), end-to-end anastomosis (n = 5; 25%, 5 out of 20). Six patients (30%, 6 out of 20) had coexisting congenital intracardiac anomalies. There were 12 pulmonary artery sling (60%, 12 out of 20) patients. Overall operative mortality was 15% (n = 3; 3 out of 20). Operative mortality was 20% (n = 2; 2 out of 10) from 1986 to 2001 and decreased to 10% (n = 1; 1 out of 10) from 2002 to 2011. All early deaths occurred in patients who had undergone patch tracheoplasty. Since 2004, there were no operative deaths. Seven patients (35%, 7 out of 20) required tracheal reintervention postoperatively. There were three late deaths (17.6%, 3 out of 17) at 8, 9 and 22 months after surgery. At last follow-up (mean 5.3 ± 6.6 years; range 1 month to 18 years), all 14 survivors remained asymptomatic. Conclusions Repair of tracheal stenosis in children has been associated with high morbidity and mortality. Since the introduction of slide tracheoplasty, a multidisciplinary team approach and abandonment of patch tracheoplasty, the mortality has been reduced. Survival beyond 2 years after surgery is associated with an excellent outcome.

Objectives Pulmonary artery (PA) sling is a rare vascular anomaly associated with congenital tracheal stenosis. The natural history is poor and these patients often require early surgical intervention. We describe our experience with repair of this condition. Methods From 1984 to 2011, 21 patients with PA sling underwent repair at the Royal Children's Hospital (median age, 5.9 months). PA sling was associated with compression of the trachea in all patients. Tracheal surgery was required in 12 (57.1%) patients. All patients had an echocardiogram, and concomitant repair of coexisting cardiac anomalies was performed in 6 (28.6%, 6/21) patients. Results Operative mortality was 14.3% (3/21), occurring at 19 days, 4.4 months, and 5 months after surgery. Operative mortality for the first 10 years was 22.2% (1984-1993; 2/9), the next 10 years was 14.3% (1994-2003; 1/7), and 0% for the most recent 7 years (2004-2011; 0/5). All deaths occurred in patients requiring tracheal repair (25%, 3/12). No deaths have occurred since 2004 with introduction of the slide tracheoplasty technique. One (5.6%, 1/18) late death occurred at 8 months after repair. After tracheal repair, intervention for excessive granulations and tracheomalacia was necessary in 6 (50%, 6/12) patients. Median follow-up was 8 years (mean, 8.6 ± 6.4 years; range, 5 months to 20.6 years), and all survivors (100%, 17/17) remain asymptomatic. Conclusions Children with PA sling who do not require tracheal surgery have excellent outcomes. Mortality is determined by the need for tracheal surgery. However, with the advent of the slide tracheoplasty technique, mortality can be reduced. Survival beyond 1 year after surgery offers excellent prognosis.

Aim Mechanical in-exsufflation (MI-E) augments the weakened cough of patients with neuromuscular disease (NMD), clearing secretions and overcoming atelectasis. Little has been published on the impact of MI-E alone on rates of hospitalisation and quality of life (QOL). The aim of this study was to assess the impact of home MI-E on hospital admissions and life-style in children with NMD. Methods A retrospective chart review was performed on children using MI-E, including data on the number of admissions to hospital, length of stay and hours of ventilation. A parental survey was used to gather information on the impact of MI-E on life-style for the child and family. Results Ten children with NMD (seven spinal muscular atrophy, two Duchenne muscular dystrophy and one centronuclear myopathy) using MI-E at home were identified. MI-E use commenced at mean age of 8.5 years (range 1.1–16.9) with 1.4 years of use (range 0.3–3.8). MI-E pressures ranged from +/−30 to 40 cmH2O with no complications reported. There was a significant reduction in hospital days at 6 (P = 0.036) and 12 (P = 0.028) months following commencement of home MI-E compared with the same period preceding MI-E use. The survey highlighted positive benefits of MI-E use, in particular the ability to treat many pulmonary exacerbations at home. Conclusions Home MI-E use by children with NMD can reduce hospitalisation and benefit families by maintaining their child at home.

Background Newborn screening allows novel treatments for cystic fibrosis (CF) to be trialled in early childhood before irreversible lung injury occurs. As respiratory exacerbations are a potential trial outcome variable, we determined their rate, duration and clinical features in preschool children with CF; and whether they were associated with growth, lung structure and function at age 5 years. Methods Respiratory exacerbations were recorded prospectively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years, when all participants underwent clinical assessment, chest CT scans and spirometry. Results 168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year; 80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p

Background Oral food challenge is the main tool for diagnosing food allergy, but there is little data on the reaction profiles of young children undergoing challenges, nor how these reactions compare to reactions on accidental ingestion in the community. Objectives To compare reaction profiles from food challenges and parent-reported reactions on accidental ingestion, and assess predictors of severe reactions. Methods HealthNuts is a longitudinal population-based cohort study of 5276 1-year-old infants. Infants underwent skin prick tests and those with identifiable wheals were offered food challenges. Food challenges were repeated at age 4 years in those with previous food allergy or reporting new food allergies. Community-reported reactions were ascertained from parent questionnaires. Results Food challenges were undertaken in 916 children at age 1 year and 357 children at age 4 years (a total of 2047 peanut, egg, or sesame challenges). Urticaria was the most common sign in positive challenges at both ages (age 1 year, 88.7%, and age 4 years, 71.2%) although angioedema was significantly more common at age 4 years (40.1%) than at age 1 year (12.9%). Anaphylaxis was equally uncommon at both ages (2.1% and 2.8% of positive challenges at ages 1 and 4 years, respectively) but more common for peanut than for egg (4.5% and 1.2% of positive challenges at ages 1 and 4 years, respectively). The patterns of presenting signs reported during community reactions were similar to those observed in formal food challenges. Serum food-specific IgE levels of 15 kU/L or more were associated with moderate to severe reactions but skin prick test was not. Conclusions There was a shift from the most common presenting reaction of urticaria during food challenges toward more angioedema in older children. Serum food-specific IgE levels were associated with reaction severity.

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

Background Tuberculosis (TB) can be prevented using isoniazid preventive therapy (IPT) among child contacts. However, the benefits of IPT depend on adherence to at least 6 months of daily treatment. A greater understanding of the barriers to and facilitators of adherence to IPT in resource-poor settings is required to optimise the benefits. Methods We prospectively evaluated adherence to IPT and its associated factors among child contacts (age 0-5 years) eligible for IPT. We undertook in-depth interviews with care givers and a focus group discussion with health care workers, which were thematically analysed to explore barriers to and facilitators of adherence from the perspective of both care givers and health workers. Results Of 99 eligible children, 49 (49.5%) did not complete 6 months of IPT. Children whose care giver collected their IPT medications from primary health centres were more likely to have incomplete adherence than those who collected them from hospitals (aOR 2.9, 95%CI 1.1-7.8). Thematic analyses revealed major barriers to and facilitators of adherence: regimen-related, care giver-related and health care-related factors, social support and access. Many of these factors are readily modifiable. Conclusion Providing information about IPT and improving accessibility for care givers to receive IPT at the primary health care facility should be priorities to facilitate implementation.

Background While the burden of chronic cough in children has been documented, etiologic factors across multiple settings and age have not been described. In children with chronic cough, we aimed (1) to evaluate the burden and etiologies using a standard management pathway in various settings, and (2) to determine the influence of age and setting on disease burden and etiologies and etiology on disease burden. We hypothesized that the etiology, but not the burden, of chronic cough in children is dependent on the clinical setting and age. Methods From five major hospitals and three rural-remote clinics, 346 children (mean age 4.5 years) newly referred with chronic cough (> 4 weeks) were prospectively managed in accordance with an evidence-based cough algorithm. We used a priori definitions, timeframes, and validated outcome measures (parent-proxy cough-specific quality of life [PC-QOL], a generic QOL [pediatric quality of life (PedsQL)], and cough diary). Results The burden of chronic cough (PC-QOL, cough duration) significantly differed between settings (P = .014, 0.021, respectively), but was not influenced by age or etiology. PC-QOL and PedsQL did not correlate with age. The frequency of etiologies was significantly different in dissimilar settings (P = .0001); 17.6% of children had a serious underlying diagnosis (bronchiectasis, aspiration, cystic fibrosis). Except for protracted bacterial bronchitis, the frequency of other common diagnoses (asthma, bronchiectasis, resolved without specific-diagnosis) was similar across age categories. Conclusions The high burden of cough is independent of children's age and etiology but dependent on clinical setting. Irrespective of setting and age, children with chronic cough should be carefully evaluated and child-specific evidence-based algorithms used. Trial registry Australian New Zealand Clinical Trials registry; No.: ACTRN12607000526471; URL: www.anzctr.org.au

To determine if respiratory function at 8 years of age in extremely low birth weight (ELBW; birth weight 2,499 g) and term (37-42 weeks) controls, particularly in those ELBW/EPT children who had bronchopulmonary dysplasia (BPD). This was a cohort study of 201 consecutive ELBW/EPT survivors born in the state of Victoria during 1997, and 199 contemporaneous randomly selected NBW/term controls. Respiratory function was measured at 8 years of age according to standard guidelines, and compared with previous cohorts born in 1991-1992. Respiratory function data were available for almost 75% of both cohorts. ELBW/EPT subjects had substantial reductions in airflow compared with controls (e.g., mean difference in forced expiratory volume in 1 sec [FEV1 ] -0.91 SD, 95% confidence interval [CI] -1.19 to -0.63 SD, and in maximum expiratory flow between 25% and 75% of vital capacity [FEF25-75% ] -0.96 SD, 95% CI -1.22 to -0.71). These differences were similar to those observed between ELBW/EPT and controls subjects born in 1991-1992. Within the ELBW/EPT cohort, children who had BPD in the newborn period had significant reductions in both the FEV1 (-0.76 SD) and FEF25-75% (-0.58 SD) compared with those who did not have BPD, which were not statistically significant from those in the 1991-92 cohort. ELBW/EPT children born in 1997 still have significantly abnormal lung function compared with NBW/term controls, but results were similar to an earlier era when survival rates were lower. Pediatr Pulmonol. 2013; 48:449-455. © 2012 Wiley Periodicals, Inc.

Objective To explore the predictors and outcome of hypoxaemia in children under 5 years of age who were hospitalized for the management of diarrhoea in Dhaka, where comorbidities are common. Methods In a prospective cohort study, we enrolled all children

PURPOSE OF REVIEW To review the theoretical background and current evidence regarding parent-initiated oral corticosteroid (PIOCS) therapy in preschool wheeze and asthma in school-aged children. RECENT FINDINGS In school-aged children with asthma PIOCS, given during acute episodes, has been associated with a modest reduction in asthma symptoms and health resource utilisation. In preschool wheeze, OCS (including PIOCS) therapy appears to be ineffective. SUMMARY PIOCS is associated with modest benefits among school-aged children with acute asthma but is not effective among children with preschool wheeze. In older children with asthma, the potential benefits of PIOCS must be balanced against potential adverse effects associated with increased OCS administration.

OBJECTIVE: Acute severe asthma in children is a common cause of admission to intensive care units (ICU), but there are few reports on long-term outcomes. This study describes outcomes for children with asthma admitted to an ICU. METHODS: All children with asthma aged 2-18 years admitted to the ICU at the Royal Children's Hospital Melbourne between 1990 and 2004 were eligible for the study. Data were collected by reviewing medical records and through telephone interviews. RESULTS: Complete data were obtained for 410 (61%) of 684 eligible patients. The mean duration of follow-up was 10.3±4.6 years. After the index admission, 67% were readmitted to hospital for asthma and 17% to the ICU. Eighty-eight per cent continued to have asthma: 46% had episodic asthma and 42% persistent asthma. Twelve patients (1.8%) subsequently died from asthma. Five per cent of those who required ventilation at their index admission died within 10 years. Risk factors for ICU readmission were admission for asthma in the preceding year (AOR 4.7; 95% CI 2.4 to 9.3) and ventilation at admission (AOR 2.4; 95% CI 1.0 to 5.3). Risk factors for subsequent mortality were multiple ICU admissions (AOR 5.0; 95% CI 1.3 to 19), persistent asthma (AOR 5.8; 95% CI 1.2 to 28.5) and ventilation at admission (AOR 4.5; 95% CI 1.3 to 15.7). CONCLUSION: Admission to the ICU for asthma is a predictor of hospital readmission. Those with persistent asthma or requiring ventilation are at significant risk of mortality in subsequent years and require close follow-up.

There are a variety of reasons why there may be an association between asthma and anxiety in children. Research into the relation between asthma and anxiety has been limited by the sole use of parent-reported or self-reported asthma symptoms to define asthma status. The objective of this study was to determine if children with physician-defined asthma are more likely to suffer anxiety than children without asthma.A population-based, cross-sectional assessment, of self-reported anxiety symptoms.Children aged 5-13 years from Barwon region of Victoria, Australia. Asthma status was determined by review with a paediatrician. Controls were a sample of children without asthma symptoms (matched for age, gender and school).The Spence Children's Anxiety Scale (SCAS) written questionnaire. The authors compared the mean SCAS score, and the proportion of children with an SCAS score in the clinical range, between the groups.Questionnaires were issued to 205 children with asthma (158 returned, response rate 77%), and 410 controls (319 returned, response rate 78%). The SCAS scores were higher in asthmatics than controls (p0.001); and were more likely to be in the clinical range (OR=2.5, 95% CI 1.1 to 5.8, p=0.036). There was no evidence that these associations could be explained by known confounding factors.Children with asthma are substantially more likely to suffer anxiety than children without asthma. Future studies are required to determine the sequence of events that leads to this comorbidity, and to test strategies to prevent and treat anxiety among children with asthma.

Objective: To improve health outcomes of children and adolescents with asthma using a multifaceted intervention for GPs. Methods:The design of the study was a cluster randomized controlled trial. GPs were randomized at a practice level in general practice clinics in Melbourne, Australia. Participants were children/adolescents aged 2-14 years with asthma and their caregivers identified from the medical records of participating clinics. Questionnaires were completed by 411 at baseline and 341 at follow-up. The intervention arm (n = 18 GPs) participated in a small group asthma education programme and was provided with locally adapted paediatric asthma guidelines. One control arm (n = 18 GPs) received only the adapted paediatric asthma guidelines, while the other control arm (n = 15 GPs) received an unrelated educational intervention. The outcome measures of the study were children/adolescents and caregivers completed questionnaires about asthma management and control, asthma knowledge and quality of life at recruitment and 6 months later. Ownership of a written asthma action plan (WAAP) was the primary outcome. Results: There was no evidence for changes in ownership of WAAPs between the three study arms. Adolescents in the intervention group reported an improvement in quality of life subscale score 'positive effects' (mean difference = 2.64, P = 0.01), but there was no evidence for an effect of the intervention on other study outcomes among the three study arms. Conclusions:The intervention was associated with some improvement in quality of life for adolescents. However, overall, the intervention did not translate into increased ownership of WAAPs, control of asthma or improved quality of life.

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

BACKGROUND: Phase I of the International Study of Asthma and Allergies in Childhood (ISAAC) was designed to allow worldwide comparisons of the prevalence of asthma symptoms. In phase III the phase I survey was repeated in order to assess changes over time. METHODS: The phase I survey was repeated after an interval of 5-10 years in 106 centres in 56 countries in children aged 13-14 years (n = 304,679) and in 66 centres in 37 countries in children aged 6-7 years (n = 193,404). RESULTS: The mean symptom prevalence of current wheeze in the last 12 months changed slightly from 13.2% to 13.7% in the 13-14 year age group (mean increase of 0.06% per year) and from 11.1% to 11.6% in the 6-7 year age group (mean increase of 0.13% per year). There was also little change in the mean symptom prevalence of severe asthma or the symptom prevalence measured with the asthma video questionnaire. However, the time trends in asthma symptom prevalence showed different regional patterns. In Western Europe, current wheeze decreased by 0.07% per year in children aged 13-14 years but increased by 0.20% per year in children aged 6-7 years. The corresponding findings per year for the other regions in children aged 13-14 years and 6-7 years, respectively, were: Oceania (-0.39% and -0.21%); Latin America (+0.32% and +0.07%); Northern and Eastern Europe (+0.26% and +0.05%); Africa (+0.16% and +0.10%); North America (+0.12% and +0.32%); Eastern Mediterranean (-0.10% and +0.79%); Asia-Pacific (+0.07% and -0.06%); and the Indian subcontinent (+0.02% and +0.06%). There was a particularly marked reduction in current asthma symptom prevalence in English language countries (-0.51% and -0.09%). Similar patterns were observed for symptoms of severe asthma. However, the percentage of children reported to have had asthma at some time in their lives increased by 0.28% per year in the 13-14 year age group and by 0.18% per year in the 6-7 year age group. CONCLUSIONS: These findings indicate that international differences in asthma symptom prevalence have reduced, particularly in the 13-14 year age group, with decreases in prevalence in English speaking countries and Western Europe and increases in prevalence in regions where prevalence was previously low. Although there was little change in the overall prevalence of current wheeze, the percentage of children reported to have had asthma increased significantly, possibly reflecting greater awareness of this condition and/or changes in diagnostic practice. The increases in asthma symptom prevalence in Africa, Latin America and parts of Asia indicate that the global burden of asthma is continuing to rise, but the global prevalence differences are lessening.