Paediatrics (RCH) - Research Publications

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    Genetic variation at the Th2 immune gene IL13 is associated with IgE-mediated paediatric food allergy
    Ashley, SE ; Tan, H-TT ; Peters, R ; Allen, KJ ; Vuillermin, P ; Dharmage, SC ; Tang, MLK ; Koplin, J ; Lowe, A ; Ponsonby, A-L ; Molloy, J ; Matheson, MC ; Saffery, R ; Ellis, JA ; Martino, D (WILEY, 2017-08)
    BACKGROUND: Food allergies pose a considerable world-wide public health burden with incidence as high as one in ten in 12-month-old infants. Few food allergy genetic risk variants have yet been identified. The Th2 immune gene IL13 is a highly plausible genetic candidate as it is central to the initiation of IgE class switching in B cells. OBJECTIVE: Here, we sought to investigate whether genetic polymorphisms at IL13 are associated with the development of challenge-proven IgE-mediated food allergy. METHOD: We genotyped nine IL13 "tag" single nucleotide polymorphisms (tag SNPs) in 367 challenge-proven food allergic cases, 199 food-sensitized tolerant cases and 156 non-food allergic controls from the HealthNuts study. 12-month-old infants were phenotyped using open oral food challenges. SNPs were tested using Cochran-Mantel-Haenszel test adjusted for ancestry strata. A replication study was conducted in an independent, co-located sample of four paediatric cohorts consisting of 203 food allergic cases and 330 non-food allergic controls. Replication sample phenotypes were defined by clinical history of reactivity, 95% PPV or challenge, and IL13 genotyping was performed. RESULTS: IL13 rs1295686 was associated with challenge-proven food allergy in the discovery sample (P=.003; OR=1.75; CI=1.20-2.53). This association was also detected in the replication sample (P=.03, OR=1.37, CI=1.03-1.82) and further supported by a meta-analysis (P=.0006, OR=1.50). However, we cannot rule out an association with food sensitization. Carriage of the rs1295686 variant A allele was also associated with elevated total plasma IgE. CONCLUSIONS AND CLINICAL RELAVANCE: We show for the first time, in two independent cohorts, that IL13 polymorphism rs1295686 (in complete linkage disequilibrium with functional variant rs20541) is associated with challenge-proven food allergy.
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    The practice and perception of precautionary allergen labelling by the Australasian food manufacturing industry
    Zurzolo, GA ; Peters, RL ; Koplin, JJ ; de Courten, M ; Mathai, ML ; Tye-Din, JA ; Tang, MLK ; Campbell, DE ; Ponsonby, A-L ; Prescott, SL ; Gurrin, L ; Dharmage, SC ; Allen, KJ (WILEY, 2017-07)
    BACKGROUND: The precautionary allergen labelling (PAL) and Voluntary Incidental Trace Allergen Labelling (VITAL® ) tools were designed by industry to assist consumers with selecting safe foods for consumption. However, a sizeable proportion of food products bear no label, and it is unclear whether these products are free from allergens and therefore safe to consume or have simply not undergone a risk assessment and therefore remain unlabelled for that reason. OBJECTIVE: To assess the prevalence of unlabelled products that have undergone a risk assessment process and to examine the factors influencing industry's uptake of the VITAL® process. METHODS: A web-based questionnaire was distributed to Australasian food and grocery manufacturers. RESULTS: One hundred and thirty-seven Australasian manufacturers were contacted, and 59 questionnaires were returned (response rate: 43%). The respondents represented 454 different manufacturing sites. Manufacturers reported that 23% (95% CI 19-28) of products (n=102/434) that had been through the VITAL® risk assessment process had no PAL statement on the label. 34% (95% CI 30-38), (n=204/600) of products that had undergone another (non-VITAL® ) risk assessment process had no PAL statement. In examining the factors that influenced industry's uptake of the VITAL® process, 25 manufacturers reported on factors that influenced the uptake of the VITAL® process, 76% (CI 95% 55-91) reported that VITAL® was an effective tool because it was based on science; 52% (CI 95% 31-72) reported that it was too time-consuming and 36% (CI 95% 18-57) identified a concern with it not being endorsed by the government. CONCLUSION AND CLINICAL RELEVANCE: Currently, we estimate that at least 30% of products may have been through a risk assessment process and yet bear no PAL statement on the label. Permissive labelling could be incorporated onto these products if they have been assessed to be safe for consumption.
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    The skin barrier function gene SPINK5 is associated with challenge-proven IgE-mediated food allergy in infants
    Ashley, SE ; Tan, H-TT ; Vuillermin, P ; Dharmage, SC ; Tang, MLK ; Koplin, J ; Gurrin, LC ; Lowe, A ; Lodge, C ; Ponsonby, A-L ; Molloy, J ; Martin, P ; Matheson, MC ; Saffery, R ; Allen, KJ ; Ellis, JA ; Martino, D (WILEY, 2017-09)
    BACKGROUND: A defective skin barrier is hypothesized to be an important route of sensitization to dietary antigens and may lead to food allergy in some children. Missense mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) skin barrier gene have previously been associated with allergic conditions. OBJECTIVE: To determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy. METHOD: We genotyped 71 "tag" single nucleotide polymorphisms (tag-SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food-allergic, n=199 food-sensitized-tolerant and n=156 non-food-allergic controls) 12-month-old infants (discovery sample) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss (TEWL) measures were collected at 12 months from a subset (n=150) of these individuals. SNPs were tested for association with food allergy using the Cochran-Mantel-Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent sample group derived from four paediatric cohorts, total n=533 (n=203 food-allergic, n=330 non-food-allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value (PPV) or challenge, corrected for ancestry by principal components. RESULTS: SPINK5 variant rs9325071 (A⟶G) was associated with challenge-proven food allergy in the discovery sample (P=.001, OR=2.95, CI=1.49-5.83). This association was further supported by replication (P=.007, OR=1.58, CI=1.13-2.20) and by meta-analysis (P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype-tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also. CONCLUSIONS: We report, for the first time, association between SPINK5 variant rs9325071 and challenge-proven IgE-mediated food allergy.
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    Formula and breast feeding in infant food allergy: A population-based study
    Goldsmith, AJ ; Koplin, JJ ; Lowe, AJ ; Tang, MLK ; Matheson, MC ; Robinson, M ; Peters, R ; Dharmage, SC ; Allen, KJ (WILEY, 2016-04)
    AIM: To determine whether infant-feeding practices, including duration of exclusive breastfeeding and use of partially hydrolysed formula, modify the risk of developing infant food allergy. METHODS: In an observational population-based study, 1 year olds were recruited from community immunisation clinics in Melbourne, Australia. Parent-reported data on infant-feeding practices and potential confounders were collected prior to infant skin prick testing for four food allergens. Sensitised infants attended hospital-based oral food challenges to establish food allergy status. Multiple logistic regression was used to investigate associations between breastfeeding and formula-feeding and infant food allergy adjusting for possible confounding variables. RESULTS: A total of 5276 (74% response) infants participated. Of the 4537 for whom food allergy status was determined, 515 (11.3%) were food allergic (challenge-proven in the context of skin prick testing positive (≥2 mm)). After adjusting for confounding variables, there was no association between duration of exclusive breastfeeding and food allergy. Use of partially hydrolysed formula did not reduce the risk of food allergy compared with cow's milk formula in the general population (adjusted odds ratios 1.03 (confidence interval 0.67-1.50)). CONCLUSION: Duration of exclusive breastfeeding and use of partially hydrolysed formula were not associated with food allergy at 1 year of age in this large population-based study. These findings have implications for population-based infant-feeding guidelines and do not support the use of partially hydrolysed formula for food allergy prevention.
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    Nut allergy prevalence and differences between Asian-born children and Australian-born children of Asian descent: a state-wide survey of children at primary school entry in Victoria, Australia
    Panjari, M ; Koplin, JJ ; Dharmage, SC ; Peters, RL ; Gurrin, LC ; Sawyer, SM ; McWilliam, V ; Eckert, JK ; Vicendese, D ; Erbas, B ; Matheson, MC ; Tang, MLK ; Douglass, J ; Ponsonby, A-L ; Dwyer, T ; Goldfeld, S ; Allen, KJ (WILEY, 2016-04)
    BACKGROUND: Asian infants born in Australia are three times more likely to develop nut allergy than non-Asian infants, and rates of challenge-proven food allergy in infants have been found to be unexpectedly high in metropolitan Melbourne. To further investigate the risk factors for nut allergy, we assessed the whole-of-state prevalence distribution of parent-reported nut allergy in 5-year-old children entering school. METHODS: Using the 2010 School Entrant Health Questionnaire administered to all 5-year-old children in Victoria, Australia, we assessed the prevalence of parent-reported nut allergy (tree nut and peanut) and whether this was altered by region of residence, socio-economic status, country of birth or history of migration. Prevalence was calculated as observed proportion with 95% confidence intervals (CI). Risk factors were evaluated using multivariable logistic regression and adjusted for appropriate confounders. RESULTS: Parent-reported nut allergy prevalence was 3.1% (95% CI 2.9-3.2) amongst a cohort of nearly 60 000 children. It was more common amongst children of mothers with higher education and socio-economic index and less prevalent amongst children in regional Victoria than in Melbourne. While children born in Australia to Asian-born mothers (aOR 2.67, 95% CI 2.28-3.27) were more likely to have nut allergy than non-Asian children, children born in Asia who subsequently migrated to Australia were at decreased risk of nut allergy (aOR 0.1, 95% CI 0.03-0.31). CONCLUSION: Migration from Asia after the early infant period appears protective for the development of nut allergy. Additionally, rural regions have lower rates of nut allergy than urban areas.
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    Timing of routine infant vaccinations and risk of food allergy and eczema at one year of age
    Kiraly, N ; Koplin, JJ ; Crawford, NW ; Bannister, S ; Flanagan, KL ; Holt, PG ; Gurrin, LC ; Lowe, AJ ; Tang, MLK ; Wake, M ; Ponsonby, A-L ; Dharmage, SC ; Allen, KJ (WILEY, 2016-04)
    BACKGROUND: Epidemiological evidence suggests that routine vaccinations can have nontargeted effects on susceptibility to infections and allergic disease. Such effects may depend on age at vaccination, and a delay in pertussis vaccination has been linked to reduced risk of allergic disease. We aimed to test the hypothesis that delay in vaccines containing diphtheria-tetanus-acellular pertussis (DTaP) is associated with reduced risk of food allergy and other allergic diseases. METHODS: HealthNuts is a population-based cohort in Melbourne, Australia. Twelve-month-old infants were skin prick-tested to common food allergens, and sensitized infants were offered oral food challenges to determine food allergy status. In this data linkage study, vaccination data for children in the HealthNuts cohort were obtained from the Australian Childhood Immunisation Register. Associations were examined between age at the first dose of DTaP and allergic disease. RESULTS: Of 4433 children, 109 (2.5%) received the first dose of DTaP one month late (delayed DTaP). Overall, delayed DTaP was not associated with primary outcomes of food allergy (adjusted odds ratio (aOR) 0.77; 95% CI: 0.36-1.62, P = 0.49) or atopic sensitization (aOR: 0.66; 95% CI: 0.35-1.24, P = 0.19). Amongst secondary outcomes, delayed DTaP was associated with reduced eczema (aOR: 0.57; 95% CI: 0.34-0.97, P = 0.04) and reduced use of eczema medication (aOR: 0.45; 95% CI: 0.24-0.83, P = 0.01). CONCLUSIONS: There was no overall association between delayed DTaP and food allergy; however, children with delayed DTaP had less eczema and less use of eczema medication. Timing of routine infant immunizations may affect susceptibility to allergic disease.
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    Infant and young child feeding interventions targeting overweight and obesity: A narrative review
    Koplin, JJ ; Kerr, JA ; Lodge, C ; Garner, C ; Dharmage, SC ; Wake, M ; Allen, KJ (WILEY, 2019-08)
    findings from systematic reviews into infant feeding and later adiposity are largely negative. World Health Organization (WHO) is auspicing Healthy Life Trajectories Initiative (HeLTI), a suite of trials aiming to prevent overweight/obesity in childhood. To inform planning, this narrative review sought to detail potentially effective components of nutrition-related interventions involving children aged 0 to 2 years. Systematic searches of PubMed and the Cochrane Library (2006-2016) identified 108 systematic reviews. These included 31 randomized trials in the age group of interest. Of these, 11 reported greater than or equal to 1 statistically significant (P < 0.05) benefit on body weight and/or composition. Six multicomponent trials whose interventions incorporated education to promote breastfeeding (four trials), responsive feeding (two trials), and healthy diet (eg, increasing fruit and vegetables and limiting unhealthy snack foods; five trials), delivered through home visits or at baby health clinics, reported relative reductions in body mass index (BMI) at the end of intervention. Early benefits were not maintained in the two trials reporting follow-up 1 to 3 years later. Other potentially effective approaches included lower protein formulas in formula-fed infants and education around reducing sugar-sweetened beverages. There is some evidence that infant feeding interventions can have a transient positive impact on a child's BMI. It is not known whether ongoing intervention can avoid the subsequent expected wash-out.
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    Age at introduction to complementary solid food and food allergy and sensitization: A systematic review and meta-analysis
    Burgess, JA ; Dharmage, SC ; Allen, K ; Koplin, J ; Garcia-Larsen, V ; Boyle, R ; Waidyatillake, N ; Lodge, CJ (WILEY, 2019-06)
    BACKGROUND AND OBJECTIVE: An infant's age at introduction of complementary solids may contribute to food allergy. We aimed to synthesize the literature on the association between age at introduction of complementary solids, excluding milk products, and food allergy and sensitization. DESIGN: We searched the electronic databases PubMed and EMBASE (January 1946-February 2017) using solid food, allergy and sensitization terms. METHODS: Two authors selected papers according to inclusion criteria, identifying 16 cohort studies, 1 case-control study and 8 randomized controlled trials (RCTs). Pooled effects across studies were estimated using random-effects meta-analysis. RESULTS: Cohort studies-Introducing complementary solids at age ≥ 4 months vs <4 months was not associated with food allergy (OR 1.22; 95% CI, 0.76-1.96) but was associated with food sensitization (OR 1.93; 95% CI 1.57-2.38). First exposure from age 4 to 6 months vs <4 months was not associated with food allergy (OR 1.01; 95% CI, 0.64-1.60) but was associated with food sensitization (OR 2.46; 95% CI 1.55-3.86). Randomized controlled trials-Egg exposure from age 4 months was associated with reduced egg allergy (OR 0.63, 95% CI, 0.44-0.90) and sensitization (OR 0.76, 95% CI, 0.51-0.95). Peanut exposure from age 4 months compared to delayed exposure was associated with reduced peanut allergy (OR 0.28, 95% CI 0.14-0.57). CONCLUSIONS: We found no evidence from observational studies that introducing solids before 4 months protected against food allergy, but there was evidence for protection against food sensitization. From RCTs, introducing egg from 4 to 6 months and peanut from 4 to 11 months reduced the risk of egg allergy, peanut allergy and egg sensitization. PROSPERO systematic review registry (CRD42016033473).
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    B-cell phenotype and function in infants with egg allergy
    Neeland, MR ; Martino, DJ ; Dang, TD ; Koplin, JJ ; Peters, RL ; Grishin, A ; Dharmage, SC ; Tang, ML ; Sampson, HA ; Saffery, R ; Allen, KJ (WILEY, 2019-05)
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    Egg allergen specific IgE diversity predicts resolution of egg allergy in the population cohort HealthNuts
    Dang, TD ; Peters, RL ; Koplin, JJ ; Dharmage, SC ; Gurrin, LC ; Ponsonby, A-L ; Martino, DJ ; Neeland, M ; Tang, MLK ; Allen, KJ (WILEY, 2019-02)
    BACKGROUND: IgE-mediated egg allergy presents as one of the most common food allergies in children. Measurement of egg white specific IgE (sIgE) levels in serum or skin prick test has been shown to be a poor predictor of clinical allergy to raw egg white, and also to baked or cooked egg. Recent developments in component resolved diagnostic (CRD) technology have enabled us to improve the way in which we diagnose and predict peanut allergy by examining IgE specificity to individual peptides. OBJECTIVES: We aimed to investigate whether egg CRD could improve current methods to diagnose various egg allergy phenotypes as well as predict the development of tolerance to egg. METHODS: Using the HealthNuts cohort of food challenge-proven egg allergic and egg-sensitized and egg-tolerant, age-matched 12-month infants with longitudinal follow-up at 2 and 4 years (n = 451), we measured serum egg white, Gal d 1, 2, 3 and 5 sIgE using ImmunoCAP. RESULTS: Gal d 1 sensitization increased the risk of persistent egg allergy by 2.5-fold. The production of sIgE to all four egg allergens (Gal d 1, 2, 3 or 5) increased the risk of having persistent raw egg allergy fourfold (OR 4.19 (95% CI: 1.25-14.07). We did not find any improvements of using Gal d 1, 2, 3 or 5 to diagnose current egg allergy compared to egg white sIgE. CONCLUSION: Sensitization to multiple egg allergens Gal d 1, 2, 3 or 5 may be a prognostic marker that could be useful for patient management and identifying individuals at risk of developing persistent egg allergy.