Paediatrics (RCH) - Research Publications
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ItemA Prospective Evaluation of the Symptom-Based Screening Approach to the Management of Children Who Are Contacts of Tuberculosis Cases(OXFORD UNIV PRESS INC, 2015-01-01)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 (<5 years) who received isoniazid preventive therapy (IPT) had developed disease compared with 4 of 149 (2.6%) asymptomatic older children who did not receive IPT. CONCLUSIONS: Symptom-based screening is an effective and simple approach to child tuberculosis contact management that can be implemented at the primary healthcare level.
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ItemBody mass index and vigorous physical activity in children and adolescents: an international cross-sectional study.(Wiley, 2017-08)AIM: To examine the relationship between reported vigorous physical activity (VPA) and body mass index (BMI) in children (6-7 years) and adolescents (13-14 years). METHODS: In the International Study of Asthma and Allergies in Childhood Phase Three, 75 895 children's parents and 199 502 adolescents answered questions relating to VPA, height and weight. The association between VPA and BMI was analysed using general linear models, adjusting for country gross national index. RESULTS: Compared to children who undertook no VPA, those in the infrequent group (once or twice per week) and those in the frequent group (three or more times per week) had mean (95% CI) BMI values 0.07 kg/m2 (0.03-0.11) and 0.09 kg/m2 (0.03-0.15) greater, respectively (p = 0.001). Compared to adolescents reporting no VPA, those in the infrequent group had a BMI 0.19 kg/m2 (0.15-0.23) greater while those in the frequent group had a BMI 0.01 kg/m2 (-0.03-0.05) greater (p < 0.0001). CONCLUSION: Reported VPA is not associated with lower BMI among children and adolescents. Investigation of VPA and BMI may be best undertaken in conjunction with other variables in the energy expenditure equation. A focus on VPA alone may be an inefficient way to manage BMI.
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ItemA mixed-methods evaluation of adherence to preventive treatment among child tuberculosis contacts in Indonesia(INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D), 2016-08)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.
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ItemNo Preview AvailableMulti-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis(NATURE PUBLISHING GROUP, 2015-12)Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.
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ItemBronchiectasis exacerbation study on azithromycin and amoxycillin-clavulanate for respiratory exacerbations in children (BEST-2): study protocol for a randomized controlled trial(BMC, 2013-02-20)BACKGROUND: Bronchiectasis unrelated to cystic fibrosis (CF) is being increasingly recognized in children and adults globally, both in resource-poor and in affluent countries. However, high-quality evidence to inform management is scarce. Oral amoxycillin-clavulanate is often the first antibiotic chosen for non-severe respiratory exacerbations, because of the antibiotic-susceptibility patterns detected in the respiratory pathogens commonly associated with bronchiectasis. Azithromycin has a prolonged half-life, and with its unique anti-bacterial, immunomodulatory, and anti-inflammatory properties, presents an attractive alternative. Our proposed study will test the hypothesis that oral azithromycin is non-inferior (within a 20% margin) to amoxycillin-clavulanate at achieving resolution of non-severe respiratory exacerbations by day 21 of treatment in children with non-CF bronchiectasis. METHODS: This will be a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel group trial involving six Australian and New Zealand centers. In total, 170 eligible children will be stratified by site and bronchiectasis etiology, and randomized (allocation concealed) to receive: 1) azithromycin (5 mg/kg daily) with placebo amoxycillin-clavulanate or 2) amoxycillin-clavulanate (22.5 mg/kg twice daily) with placebo azithromycin for 21 days as treatment for non-severe respiratory exacerbations. Clinical data and a parent-proxy cough-specific quality of life (PC-QOL) score will be obtained at baseline, at the start and resolution of exacerbations, and on day 21. In most children, blood and deep-nasal swabs will also be collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 21. The main secondary outcome is the PC-QOL score. Other outcomes are: time to next exacerbation; requirement for hospitalization; duration of exacerbation, and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood inflammatory markers will be reported where available. DISCUSSION: Currently, there are no published randomized controlled trials (RCT) to underpin effective, evidence-based management of acute respiratory exacerbations in children with non-CF bronchiectasis. To help address this information gap, we are conducting two RCTs. The first (bronchiectasis exacerbation study; BEST-1) evaluates the efficacy of azithromycin and amoxycillin-clavulanate compared with placebo, and the second RCT (BEST-2), described here, is designed to determine if azithromycin is non-inferior to amoxycillin-clavulanate in achieving symptom resolution by day 21 of treatment in children with acute respiratory exacerbations. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR) number http://ACTRN12612000010897. http://www.anzctr.org.au/trial_view.aspx?id=347879.
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ItemProspective evaluation of respiratory exacerbations in children with cystic fibrosis from newborn screening to 5 years of age(BMJ PUBLISHING GROUP, 2013-07)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<0.001) per year of age. Exacerbation rate differed by site (p<0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospital-managed exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient -0.39, 95% CI -0.74 to -0.05). CONCLUSIONS: Respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group.
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ItemAntibiotics for bronchiectasis exacerbations in children: rationale and study protocol for a randomised placebo-controlled trial(BMC, 2012-08-31)BACKGROUND: Despite bronchiectasis being increasingly recognised as an important cause of chronic respiratory morbidity in both indigenous and non-indigenous settings globally, high quality evidence to inform management is scarce. It is assumed that antibiotics are efficacious for all bronchiectasis exacerbations, but not all practitioners agree. Inadequately treated exacerbations may risk lung function deterioration. Our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis. METHODS: We are conducting a bronchiectasis exacerbation study (BEST), which is a multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group trial, in five centres (Brisbane, Perth, Darwin, Melbourne, Auckland). In the component of BEST presented here, 189 children fulfilling inclusion criteria are randomised (allocation-concealed) to receive amoxicillin-clavulanic acid (22.5 mg/kg twice daily) with placebo-azithromycin; azithromycin (5 mg/kg daily) with placebo-amoxicillin-clavulanic acid; or placebo-azithromycin with placebo-amoxicillin-clavulanic acid for 14 days. Clinical data and a paediatric cough-specific quality of life score are obtained at baseline, at the start and resolution of exacerbations, and at day 14. In most children, blood and deep nasal swabs are also collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 14. The main secondary outcome is the paediatric cough-specific quality of life score. Other outcomes are time to next exacerbation; requirement for hospitalisation; duration of exacerbation; and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood markers will also be reported. DISCUSSION: Effective, evidence-based management of exacerbations in people with bronchiectasis is clinically important. Yet, there are few randomised controlled trials (RCTs) in the neglected area of non-cystic fibrosis bronchiectasis. Indeed, no published RCTs addressing the treatment of bronchiectasis exacerbations in children exist. Our multicentre, double-blind RCT is designed to determine if azithromycin and amoxicillin-clavulanic acid, compared with placebo, improve symptom resolution on day 14 in children with acute respiratory exacerbations. Our planned assessment of the predictors of antibiotic response, the role of antibiotic-resistant respiratory pathogens, and whether early treatment with antibiotics affects duration and time to the next exacerbation, are also all novel. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR) number ACTRN12612000011886.
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ItemGenome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA(PUBLIC LIBRARY SCIENCE, 2012-09-28)RATIONALE: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. OBJECTIVES: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. METHODS: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5 x 10(-8)) and three variants reported as suggestive (P<5× 10(-7)). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. MAIN RESULTS: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4 × 10(-9)). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (P(Stage1+Stage2) = 1.1x10(-9)), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P(Stage1+Stage2) = 1.1x10(-8)), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. CONCLUSIONS: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
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ItemCan a management pathway for chronic cough in children improve clinical outcomes: protocol for a multicentre evaluation(BIOMED CENTRAL LTD, 2010-11-06)BACKGROUND: Chronic cough is common and is associated with significant economic and human costs. While cough can be a problematic symptom without serious consequences, it could also reflect a serious underlying illness. Evidence shows that the management of chronic cough in children needs to be improved. Our study tests the hypothesis that the management of chronic cough in children with an evidence-based management pathway is feasible and reliable, and improves clinical outcomes. METHODS/DESIGN: We are conducting a multicentre randomised controlled trial based in respiratory clinics in 5 major Australian cities. Children (n = 250) fulfilling inclusion criteria (new patients with chronic cough) are randomised (allocation concealed) to the standardised clinical management pathway (specialist starts clinical pathway within 2 weeks) or usual care (existing care until review by specialist at 6 weeks). Cough diary, cough-specific quality of life (QOL) and generic QOL are collected at baseline and at 6, 10, 14, 26, and 52 weeks. Children are followed-up for 6 months after diagnosis and cough resolution (with at least monthly contact from study nurses). A random sample from each site will be independently examined to determine adherence to the pathway. Primary outcomes are group differences in QOL and proportion of children that are cough free at week 6. DISCUSSION: The clinical management pathway is based on data from Cochrane Reviews combined with collective clinical experience (250 doctor years). This study will provide additional evidence on the optimal management of chronic cough in children. TRIAL REGISTRATION: ACTRN12607000526471.
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ItemMeta-analysis identifies seven susceptibility loci involved in the atopic march(NATURE PUBLISHING GROUP, 2015-11)Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.