Paediatrics (RCH) - Research Publications
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ItemThe longitudinal impact of probiotic and peanut oral immunotherapy on health-related quality of life(WILEY, 2018-03)BACKGROUND: We previously reported that probiotic and peanut oral immunotherapy (PPOIT) was effective at inducing sustained unresponsiveness compared with placebo in a double-blind, placebo-controlled randomized trial. This study evaluated the impact of PPOIT on health-related quality of life (HRQL). METHOD: Fifty-one participants (PPOIT 24; placebo 27) from the PPOIT trial completed Food Allergy Quality of Life Questionnaire (FAQLQ-PF) and Food Allergy Independent Measure (FAIM) at pre-treatment, end-of-treatment and 3 months after end-of-treatment. A total of 42 participants (20 PPOIT; 22 placebo) completed measures at 12 months post-treatment. Changes over time in PPOIT and placebo groups were examined by repeated-measures analysis of variance and paired t tests. RESULTS: Probiotic and peanut oral immunotherapy was associated with significant improvement in FAQLQ-PF (F = 3.63, P = .02), with mean difference 0.8 at 3 months post-treatment (P = .05) and 1.3 at 12 months post-treatment (P = .005), exceeding the 0.5 minimal clinically important difference for FAQLQ-PF. For FAIM, mean difference was 0.5 (P = .03) at 3 months and 0.4 (P = .04) at 12 months post-treatment. In placebo group, post-treatment FAQLQ and FAIM remained unchanged from pretreatment. Improvement in FAQLQ-PF and FAIM scores related specifically to acquisition of sustained unresponsiveness rather than to receiving PPOIT treatment or participation in the trial. CONCLUSIONS: Probiotic and peanut oral immunotherapy has a sustained beneficial effect on psychosocial impact of food allergy at 3 and 12 months after end-of-treatment. Treatment was not associated with reduced HRQL relative to baseline in either PPOIT or placebo groups, indicating that PPOIT was well tolerated and psychological well-being was not negatively impacted. Improved HRQL was specifically associated with acquisition of sustained unresponsiveness.
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ItemPrevalence and determinants of antibiotic exposure in infants: A population-derived Australian birth cohort study(WILEY, 2017-10)AIM: The aim of this study was to describe antibiotic exposure in Australian infants during the first year of life, focusing on antibiotic class, indication, risk factors associated with exposure and comparison with international counterparts. METHODS: The Barwon Infant Study is a birth cohort study (n = 1074) with an unselected antenatal sampling frame from a large regional centre in Victoria, Australia. Longitudinal data on infection and medication were collected at 1, 3, 6, 9 and 12 months by parental questionnaire and from general practitioner and hospital records. Predictors of questionnaire non-completion were identified. A total of 660 infants with complete serial data were comprehensively examined. Antibiotic exposure was calculated as (i) antibiotic prescriptions and (ii) antibiotic days-exposed per person-year. RESULTS: Mean antibiotic prescription rate was 0.92 prescriptions (95% confidence interval (CI), 0.83-1.02) per person-year, with the highest rates in those aged <1 month (1.50 (95% CI, 1.09-1.91) per person-year). A total of 50.0% of infants were exposed to at least one antibiotic in their first year of life. Increasing number of siblings was associated with increased antibiotic exposure. Penicillin with extended spectrum (365 of 661 antibiotic prescriptions, 52.6%) and cephalosporins (12.0%) were the most frequently prescribed antibiotics. One fifth of antibiotics were prescribed for respiratory tract infections and bronchiolitis. CONCLUSION: Australian infants in this large population-based study are exposed to considerably more antibiotics than the majority of their international counterparts. Interventions aimed at addressing avoidable prescribing by medical practitioners and modifiable risk factors associated with antibiotic exposure may reduce antibiotic use.
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ItemGenetic variation at the Th2 immune gene IL13 is associated with IgE-mediated paediatric food allergy(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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ItemThe practice and perception of precautionary allergen labelling by the Australasian food manufacturing industry(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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ItemThe skin barrier function gene SPINK5 is associated with challenge-proven IgE-mediated food allergy in infants(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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ItemFood allergy: is prevalence increasing?(WILEY, 2017-03)It is generally accepted that the prevalence of food allergy has been increasing in recent decades, particularly in westernised countries, yet high-quality evidence that is based on challenge confirmed diagnosis of food allergy to support this assumption is lacking because of the high cost and potential risks associated with conducting food challenges in large populations. Accepting this caveat, the use of surrogate markers for diagnosis of food allergy (such as nationwide data on hospital admissions for food anaphylaxis or clinical history in combination with allergen-specific IgE (sIgE) measurement in population-based cohorts) has provided consistent evidence for increasing prevalence of food allergy at least in western countries, such as the UK, United States and Australia. Recent reports that children of East Asian or African ethnicity who are raised in a western environment (Australia and United States respectively) have an increased risk of developing food allergy compared with resident Caucasian children suggest that food allergy might also increase across Asian and African countries as their economies grow and populations adopt a more westernised lifestyle. Given that many cases of food allergy persist, mathematical principles would predict a continued increase in food allergy prevalence in the short to medium term until such time as an effective treatment is identified to allow the rate of disease resolution to be equal to or greater than the rate of new cases.
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ItemVitamin D insufficiency in the first 6 months of infancy and challenge-proven IgE-mediated food allergy at 1 year of age: a case-cohort study(WILEY, 2017-08)BACKGROUND: Ecological evidence suggests vitamin D insufficiency (VDI) due to lower ambient ultraviolet radiation (UVR) exposure may be a risk factor for IgE-mediated food allergy. However, there are no studies relating directly measured VDI during early infancy to subsequent challenge-proven food allergy. OBJECTIVE: To prospectively investigate the association between VDI during infancy and challenge-proven food allergy at 1 year. METHODS: In a birth cohort (n = 1074), we used a case-cohort design to compare 25-hydroxyvitamin D3 (25(OH)D3 ) levels among infants with food allergy vs a random subcohort (n = 274). The primary exposures were VDI (25(OH)D3 <50 nM) at birth and 6 months of age. Ambient UVR and time in the sun were combined to estimate UVR exposure dose. IgE-mediated food allergy status at 1 year was determined by formal challenge. Binomial regression was used to examine associations between VDI, UVR exposure dose and food allergy and investigate potential confounding. RESULTS: Within the random subcohort, VDI was present in 45% (105/233) of newborns and 24% (55/227) of infants at 6 months. Food allergy prevalence at 1 year was 7.7% (61/786), and 6.5% (53/808) were egg-allergic. There was no evidence of an association between VDI at either birth (aRR 1.25, 95% CI 0.70-2.22) or 6 months (aRR 0.93, 95% CI 0.41-2.14) and food allergy at 1 year. CONCLUSIONS: There was no evidence that VDI during the first 6 months of infancy is a risk factor for food allergy at 1 year of age. These findings primarily relate to egg allergy, and larger studies are required.
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ItemEarly gut colonization by Bifidobacterium breve and B. catenulatum differentially modulates eczema risk in children at high risk of developing allergic disease(WILEY, 2016-12)BACKGROUND: An altered compositional signature and reduced diversity of early gut microbiota are linked to development of allergic disease. We investigated the relationship between dominant Bifidobacterium species during the early post-natal period and subsequent development of allergic disease in the first year of life. METHODS: Faecal samples were collected at age 1 week, 1 month and 3 months from 117 infants at high risk of allergic disease. Bifidobacterium species were analysed by quantitative PCR and terminal restriction fragment length polymorphism. Infants were examined at 3, 6 and 12 months, and skin prick test was performed at 12 months. Eczema was diagnosed according to the UK Working Party criteria. RESULTS: The presence of B. catenulatum at 3 months was associated with a higher risk of developing eczema (ORadj = 4.5; 95% CI: 1.56-13.05, padj = 0.005). Infants colonized with B. breve at 1 week (ORadj = 0.29; 95% CI: 0.09-0.95, padj = 0.04) and 3 months (ORadj = 0.15; 95% CI: 0.05-0.44, padj = 0.00001) had a reduced risk of developing eczema. Furthermore, the presence of B. breve at 3 months was associated with a lower risk of atopic sensitization at 12 months (ORadj = 0.38; 95% CI: 0.15-0.98, padj = 0.05). B. breve colonization patterns were influenced by maternal allergic status, household pets and number of siblings. CONCLUSIONS: Temporal variations in Bifidobacterium colonization patterns early in life are associated with later development of eczema and/or atopic sensitization in infants at high risk of allergic disease. Modulation of the early microbiota may provide a means to prevent eczema in high-risk infants.
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ItemThe association between higher maternal pre-pregnancy body mass index and increased birth weight, adiposity and inflammation in the newborn(WILEY, 2018-01)BACKGROUND: Excess adiposity and adiposity-related inflammation are known risk factors for cardiovascular disease in adults; however, little is known regarding the determinants of adiposity-related inflammation at birth. OBJECTIVES: The aim of this study was to investigate the association between maternal pre-pregnancy BMI and newborn adiposity and inflammation. METHODS: Paired maternal (28-week gestation) and infant (umbilical cord) blood samples were collected from a population-derived birth cohort (Barwon Infant Study, n = 1074). Data on maternal comorbidities and infant birth anthropomorphic measures were compiled, and infant aortic intima-media thickness was measured by trans-abdominal ultrasound. In a selected subgroup of term infants (n = 161), matched maternal and cord lipids, high-sensitivity C-reactive protein (hsCRP) and maternal soluble CD14 were measured. Analysis was completed by using pairwise correlation and linear regression. Because of their non-normal distribution, pathology blood measures were log transformed prior to analysis. RESULTS: Maternal pre-pregnancy BMI was positively associated with increased birth weight (mean difference 17.8 g per kg m-2 , 95% CI 6.6 to 28.9; p = 0.002), newborn mean skin-fold thickness (mean difference 0.1 mm per kg m-2 , 95% CI 0.0 to 0.1; p < 0.001) and cord blood hsCRP (mean difference of 4.2% increase in hsCRP per kg m-2 increase in pre-pregnancy BMI, 95% CI 0.6 to 7.7%, p = 0.02), but not cord blood soluble CD14. Inclusion of maternal hsCRP as a covariate attenuated the associations between pre-pregnancy BMI and both newborn skin-fold thickness and cord blood hsCRP. CONCLUSION: Higher maternal pre-pregnancy BMI is associated with increased newborn adiposity and inflammation. These associations may be partially mediated by maternal inflammation during pregnancy.