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Introduction: Children with peanut allergy are at increased risk of developing tree nut allergies, which can be severe and for most lifelong. Introduction of peanut in the first year of life can reduce the risk of peanut allergy, however, prevention strategies for tree nut allergies have not been established. We aimed to test the efficacy and safety of a novel strategy, a supervised multi-nut oral food challenge (OFC) compared to standard care for tree nut allergy prevention in infants at high risk of developing tree nut allergy, TreEAT. Methods and analysis: TreEAT is a 2-armed, open-label, randomised, controlled trial (RCT). Infants (n=212) aged 4-11months with peanut allergy will be randomised 1:1 at peanut allergy diagnosis to either a hospital-based multi-tree nut (almond, cashew, hazelnut and walnut) OFC using multi-nut butter or standard care (home introduction of individual tree nuts). All infants will be assessed at age 18months, with questionnaires and SPT to peanut and tree nuts. Peanut and tree nut OFCs will be performed as required to determine allergy status for each nut. The primary outcome is tree nut allergy at age 18 months. Secondary outcomes include peanut allergy resolution, proportion and severity of adverse events related to tree nut ingestion, number and frequency of tree nuts ingested, quality of life and parental anxiety and allergy related healthcare visits from randomisation to 18 months of age. Analyses will be performed on an intention-to-treat basis. Ethics and dissemination TreEAT was approved by the Royal Children’s Hospital Human Research Ethics Committee (#70489). Outcomes will be presented at scientific conferences and disseminated through publication. Trial registration number: ClinicalTrials.gov ID: NCT04801823

Research Letter There are few data on long-term effects and quality of life impact of peanut OIT. PPOIT was shown to induce 8-week sustained unresponsiveness that persists to 3-years post-treatment after ad libitum peanut ingestion. PPOIT provides lasting benefits for children with peanut allergy, with long-lasting improvement in health-related quality of life.

IntroductionEgg allergy is the most common food allergy in children but recent studies have shown persistence or delayed resolution into adolescence. As there is currently no effective long-term treatment, definitive treatments that improve quality of life and prevent fatalities for food allergies are required. We have previously shown that a novel treatment comprising a combination of the probiotic Lactobacillus rhamnosus CGMCC 1.3724 with peanut oral immunotherapy (OIT) is highly effective at inducing sustained unresponsiveness, with benefit persisting to 4 years after treatment cessation in the majority of initial treatment responders. In this study, we plan to extend the probiotic food OIT platform to another allergen, namely egg. We describe the protocol for a phase 2, dual-centre, randomised, controlled trial evaluating the effectiveness of probiotic and egg OIT at inducing desensitisation or sustained unresponsiveness (remission) in participants with egg allergy compared with placebo.Methods and analysis80 participants aged 5–30 years of age with current egg allergy confirmed by double-blind placebo-controlled food challenge at study screening will be recruited from Australia and Singapore. There are two intervention arms—probiotic and egg OIT (active) or placebo. Interventions are administered once daily for 18 months. The primary outcome is the proportion of participants who attain 8-week sustained unresponsiveness in the active group versus placebo group.Ethics and disseminationThis study has been approved by the Human Research Ethics Committees at the Royal Children’s Hospital (HREC 2019.082) and the National Healthcare Group Domain Specific Review Board (2019/00029). Results will be published in peer-reviewed journals and disseminated via presentations at international conferences.Trial registration numberACTRN12619000480189.

SummaryBackground It is controversial whether egg-allergic children should strictly avoid all forms of egg, or if regular ingestion of baked egg will either delay or hasten the resolution of egg allergy. Objective This is the first study to examine the relationship between frequency of baked egg ingestion and rate of decline in egg skin prick test size in egg-allergic children. Methodology This was a retrospective clinical cohort study. All children with challenge-proven egg allergy who attended the Royal Children's Hospital Allergy Department 1996–2005 and had at least two egg skin prick tests performed in this period were included (n = 125). Frequency of baked egg ingestion was assessed by telephone questionnaire as follows: (a) frequent (> once per week), (b) regular (> once every 3 months, up to ≤ once per week) or (c) strict avoidance (≤ once every 3 months). The relationship between frequency of baked egg ingestion and rate of decline in egg skin prick test size was examined by multiple linear regression, adjusting for potential confounders. Results Mean rate of decline in egg skin prick test size in all children was 0.7 mm/year (95% CI 0.5–1.0 mm/year). There was no evidence (P = 0.57) that the rate of decline in egg skin prick test size differed between children who undertook frequent ingestion (n = 21, mean 0.4 mm/year, 95% CI −0.3–1.2 mm/year), regular ingestion (n = 37, mean 0.9 mm/year, 95% CI 0.4–1.4 mm/year) or strict avoidance (n = 67, mean 0.7 mm/year, 95% CI 0.4–1.1 mm/year) of baked egg. Conclusions Compared with strict dietary avoidance, frequent consumption of baked egg was not associated with a different rate of decline in egg skin prick test size in egg-allergic children. Clinical Relevance Given that dietary restrictions can adversely impact on the family, it is reasonable to consider liberalizing baked egg in the diet of egg-allergic children.

BACKGROUND: Measurement of whole peanut-specific IgE (sIgE) is often used to confirm sensitization but does not reliably predict allergy. Ara h 2 is the dominant peanut allergen detected in 90% to 100% of patients with peanut allergy and could help improve diagnosis. OBJECTIVES: We sought to determine whether Ara h 2 testing might improve the accuracy of diagnosing peanut allergy and therefore circumvent the need for an oral food challenge (OFC). METHODS: Infants from the population-based HealthNuts study underwent skin prick tests to determine peanut sensitization and subsequently underwent a peanut OFC to confirm allergy status. In a stratified random sample of 200 infants (100 with peanut allergy and 100 with peanut tolerance), whole peanut sIgE and Ara h 2 sIgE levels were quantified by using fluorescence enzyme immunoassay. RESULTS: By using the previously published 95% positive predictive value of 15 kU(A)/L for whole peanut sIgE, a corresponding specificity of 98% (95% CI, 93% to 100%) was found in this study cohort. At the equivalent specificity of 98%, the sensitivity of Ara h 2 sIgE is 60% (95% CI, 50% to 70%), correctly identifying 60% of subjects with true peanut allergy compared with only 26% correctly identified by using whole peanut sIgE. We report that when using a combined approach of plasma sIgE testing for whole peanut followed by Ara h 2 for the diagnosis of peanut allergy, the number of OFCs required is reduced by almost two thirds. CONCLUSION: Ara h 2 plasma sIgE test levels provide higher diagnostic accuracy than whole peanut plasma sIgE levels and could be considered a new diagnostic tool to distinguish peanut allergy from peanut tolerance, which might reduce the need for an OFC.

In recent times, allergy has become a financial, physical andpsychological burden to the society as a whole. Allergic reactions can result in life-threatening situations causing morbidity and high economic cost. Therefore, more effective reagents are needed for allergy treatment. Literature suggests that a causal relationship exists between the intake of Omega-3/6 fatty acids such as DHA, EPA, DPA and AA and atopic individuals suffering from allergies. In an allergic cascade, cytokines IL-4 and IL-13 bind to IL-4 receptor (IL-4R), which activates the STAT6 phosphorylation pathway leading to gene activation of allergen-specific IgE production by B cells. The overall aim of this study is to characterise Omega-3/6 fatty acids and their effects on IgE production.

A limited number of adrenaline auto-injectors are currently available. Epipen and Anapen are available in Australia, New Zealand, UK and parts of Europe and Asia. Few studies have compared the performance of these devices.To compare the intuitiveness of use of these devices. A secondary aim was to compare the ability to recall the use of each device after a period of 3 months.A random sample of 100 subjects naïve to both the EpiPen and Anapen were recruited from staff and families attending Royal Children's Hospital, Melbourne Australia. Subjects were randomized to Anapen (n = 53) or EpiPen (n = 47) and asked to demonstrate use of a 'trainer' device (i) prior to and (ii) after receiving training in its correct use. A subset (n = 32) participated in a follow-up study to evaluate (iii) the ability to recall correct use of each device.Most subjects correctly demonstrated all steps in use of the EpiPen and Anapen both prior to (89% vs. 79%, p = 0.17) and after training on use (100% vs. 100%). However, after 3 months, significantly more participants correctly demonstrated use of EpiPen (87%) compared to Anapen (35%) (p = 0.003) and critical errors that would likely result in failure to administer adrenaline were more common with Anapen (59% vs. 13%, p = 0.01).Most study participants correctly demonstrated the use of both devices without prior training. There was greater attrition in correct use of Anapen compared to EpiPen over time. Critical errors in administration were more likely with Anapen than EpiPen.

Background: Socio-demographic predictors for the development of clinically observed, infantile eczema have not been formally examined in a large population-based study. Few studies of eczema risk factors have included current, objective eczema outcomes as well as parent-reported history. Objectives: We aimed to measure the population prevalence of infantile eczema using novel sampling methodology, and identify socio-demographic risk factors for eczema in the first year of life. Methods: A population-based cross-sectional study of infantile allergy (the HealthNuts study, n = 4972, response rate 74.1%) was conducted from 2008-2011 in Melbourne, Australia. Infants were examined for current eczema at age 12 months (mean 12.7, SD 0.7). Parents provided information about the infants' history of eczema and demographic factors. Factors associated with eczema were modelled using multinomial logistic regression. Results: The population prevalence of observed eczema at 12 months was 20.3% (95% CI 19.0, 21.5), while cumulative prevalence for parent-reported eczema was 28.0% (95% CI 26.7, 29.4). The strongest predictors of eczema were maternal eczema and asthma (multinomial (M)-OR 1.7, P < 0.001, and M-OR 1.4, P = 0.007), male sex (M-OR 1.4, P < 0.001), and East Asian ethnicity (M-OR 1.6, P < 0.001) with over 80% of infants with all risk factors exhibiting eczema. East Asian parents, particularly recent migrants, reported fewer allergies than other parents. Conclusions and Clinical Relevance: Approximately, one in three infants developed eczema by 12 months of age. East Asian infants are at increased risk of eczema despite their parents having lower rates of allergy than non-Asian parents. Gene-environment interactions may explain the differential effect seen in this minority group.

Background Infant feeding guidelines have long recommended delaying introduction of solids and allergenic foods to prevent allergy in high-risk infants, despite a paucity of evidence. Objective We aimed to determine whether confirmed egg allergy in 12-month-old infants is associated with (1) duration of breast-feeding and (2) ages of introducing egg and solids. Methods In a population-based cross-sectional study (HealthNuts) parents reported on infant feeding and potential confounding factors before skin prick testing for egg white. Egg-sensitized infants were then offered an egg oral food challenge. Multiple logistic regression was used to investigate associations between diet and egg allergy adjusted for possible confounding factors. Results A total of 2589 infants (73% response) participated. Compared with introduction at 4 to 6 months, introducing egg into the diet later was associated with higher risks of egg allergy (adjusted odds ratios [ORs], 1.6 [95% CI, 1.0-2.6] and 3.4 [95% CI, 1.8-6.5] for introduction at 10-12 and after 12 months, respectively). These findings persisted even in children without risk factors (OR, 3.3 [95% CI, 1.1-9.9]; 10-12 months). At age 4 to 6 months, first exposure as cooked egg reduced the risk of egg allergy compared with first exposure as egg in baked goods (OR, 0.2 [95% CI, 0.06-0.71]). Duration of breast-feeding and age at introduction of solids were not associated with egg allergy. Conclusions Introduction of cooked egg at 4 to 6 months of age might protect against egg allergy. Changes in infant feeding guidelines could have a significant effect on childhood egg allergy and possibly food allergy more generally.

Coadministration of a bacterial adjuvant with oral immunotherapy (OIT) has been suggested as a potential treatment for food allergy.To evaluate a combined therapy comprising a probiotic together with peanut OIT.We performed a double-blind, placebo-controlled randomized trial of the probiotic Lactobacillus rhamnosus CGMCC 1.3724 and peanut OIT (probiotic and peanut oral immunotherapy [PPOIT]) in children (1-10 years) with peanut allergy. The primary outcome was induction of sustained unresponsiveness 2 to 5 weeks after discontinuation of treatment (referred to as possible sustained unresponsiveness). Secondary outcomes were desensitization, peanut skin prick test, and specific IgE and specific IgG4 measurements.Sixty-two children were randomized and stratified by age (≤5 and5 years) and peanut skin test wheal size (≤10 and10 mm); 56 reached the trial's end. Baseline demographics were similar across groups. Possible sustained unresponsiveness was achieved in 82.1% receiving PPOIT and 3.6% receiving placebo (P.001). Nine children need to be treated for 7 to achieve sustained unresponsiveness (number needed to treat, 1.27; 95% CI, 1.06-1.59). Of the subjects, 89.7% receiving PPOIT and 7.1% receiving placebo were desensitized (P.001). PPOIT was associated with reduced peanut skin prick test responses and peanut-specific IgE levels and increased peanut-specific IgG4 levels (all P.001). PPOIT-treated participants reported a greater number of adverse events, mostly with maintenance home dosing.This is the first randomized placebo-controlled trial evaluating the novel coadministration of a probiotic and peanut OIT and assessing sustained unresponsiveness in children with peanut allergy. PPOIT was effective in inducing possible sustained unresponsiveness and immune changes that suggest modulation of the peanut-specific immune response. Further work is required to confirm sustained unresponsiveness after a longer period of secondary peanut elimination and to clarify the relative contributions of probiotics versus OIT.

Background There is a paucity of data examining the natural history of and risk factors for egg allergy persistence, the most common IgE-mediated food allergy in infants. Objective We aimed to assess the natural history of egg allergy and identify clinical predictors for persistent egg allergy in a population-based cohort. Methods The HealthNuts study is a prospective, population-based cohort study of 5276 infants who underwent skin prick tests to 4 allergens, including egg. Infants with a detectable wheal were offered hospital-based oral food challenges (OFCs) to egg, irrespective of skin prick test wheal sizes. Infants with challenge-confirmed raw egg allergy were offered baked egg OFCs at age 1 year and follow-up at age 2 years, with repeat OFCs to raw egg. Results One hundred forty infants with challenge-confirmed egg allergy at age 1 year participated in the follow-up. Egg allergy resolved in 66 (47%) infants (95% CI, 37% to 56%) by 2 years of age; however, resolution was lower in children with baked egg allergy at age 1 year compared with baked egg tolerance (13% and 56%, respectively; adjusted odds ratio, 5.27; 95% CI, 1.36-20.50; P = .02). In the subgroup of infants who were tolerant to baked egg at age 1 year, frequent ingestion of baked egg (≥5 times per month) compared with infrequent ingestion (0-4 times per month) increased the likelihood of tolerance (adjusted odds ratio, 3.52; 95% CI, 1.38-8.98; P = .009). Mutation in the filaggrin gene was not associated with the resolution of either egg allergy or egg sensitization at age 2 years. Conclusion Phenotyping of egg allergy (baked egg tolerant vs allergic) should be considered in the management of this allergy because it has prognostic implications and eases dietary restrictions. Randomized controlled trials for egg oral immunotherapy should consider stratifying at baseline by the baked egg subphenotype to account for the differential rate of tolerance development.

Background Epidemiological evidence has shown that pediatric food allergy is more prevalent in regions further from the equator, suggesting that vitamin D insufficiency may play a role in this disease. Objective To investigate the role of vitamin D status in infantile food allergy. Methods A population sample of 5276 one-year-old infants underwent skin prick testing to peanut, egg, sesame, and cow's milk or shrimp. All those with a detectable wheal and a random sample of participants with negative skin prick test results attended a hospital-based food challenge clinic. Blood samples were available for 577 infants (344 with challenge-proven food allergy, 74 sensitized but tolerant to food challenge, 159 negative on skin prick test and food challenge). Serum 25-hydroxyvitamin D levels were measured by using liquid chromatography tandem mass spectrometry. Associations between serum 25-hydroxyvitamin D and food allergy were examined by using multiple logistic regression, adjusting for potential risk and confounding factors. Results Infants of Australian-born parents, but not of parents born overseas, with vitamin D insufficiency (≤50 nmol/L) were more likely to be peanut (adjusted odds ratio [aOR], 11.51; 95% CI, 2.01-65.79; P = .006) and/or egg (aOR, 3.79; 95% CI, 1.19-12.08; P = .025) allergic than were those with adequate vitamin D levels independent of eczema status. Among those with Australian-born parents, infants with vitamin D insufficiency were more likely to have multiple food allergies (≥2) rather than a single food allergy (aOR, 10.48; 95% CI, 1.60-68.61 vs aOR, 1.82; 95% CI, 0.38-8.77, respectively). Conclusions These results provide the first direct evidence that vitamin D sufficiency may be an important protective factor for food allergy in the first year of life.

Parents and children who have been prescribed an Epipen are often unable to demonstrate its correct administration. One contributory factor may be that doctors are unfamiliar with the EpiPen and are unable to demonstrate the correct administration of the pen to the family. The aim of this study was to determine the rate of correct EpiPen demonstration by junior and Senior Medical Staff at a major tertiary paediatric Hospital. Junior and Senior medical staff were scored on their ability to correctly use the EpiPen trainer. A 6 step scoring system was used. One-hundred doctors were recruited (Residents n = 31, Senior Residents n = 39, Fellow/Consultants n = 30). Junior and Senior Medical staff had similar scores for EpiPen demonstration, the number that needed to read the EpiPen instructions prior to use and the frequancy of accidental self-injection into the thumb. Only two doctors (2%) demonstrated all 6 administration steps correctly. The most frequent errors made were not holding the pen in place for >5 seconds (57%), failure to apply pressure to activate (21%), and self-injection into the thumb (16%). Ninety five doctors needed to read the instructions, and of these, only 39 (41%) then proceeded to correctly demonstrate the remaining 5 steps. Forty-five doctors had previously dispensed an EpiPen, but only three demonstrated its use to parents/children with a trainer. The majority of doctors do not know how to use an Epipen and are unable to provide appropriate education to parents/children. In 37% of cases, the demonstration would not have delivered adrenaline to a patient.

Background Although egg allergy is the most common food allergy in infants and young children, risk factors for egg allergy remain largely unknown. This study examined the relationship between environmental and demographic factors and egg allergy in a population-based infant cohort. Methods In a study of 5276 infants (HealthNuts), infants underwent skin prick testing (SPT) to egg white at 12 months of age. Questionnaire data on relevant exposures were obtained. 699/873 (80%) infants eligible for oral food challenge (detectable wheal on SPT) attended for formal assessment of egg allergy status; 453 had confirmed egg allergy (positive challenge and SPT ≥ 2 mm). Associations between environmental and demographic factors and egg allergy were investigated using multivariable logistic regression. Results Children with older siblings and those with a pet dog at home were less likely to develop egg allergy by 1 year of age (adjusted OR [aOR], 0.72; 95% CI, 0.62, 0.83 per sibling; and aOR, 0.72; 95% CI, 0.52, 0.99, respectively). Caesarean section delivery, antibiotic use in infancy, childcare attendance and maternal age were not associated with egg allergy. History of allergic disease in an immediate family member and having parents born in East Asia were strong risk factors for infantile egg allergy (aOR, 1.82; 95% CI, 1.40, 2.36; and aOR, 3.30; 95% CI, 2.45, 4.45, respectively). Conclusions Exposure in the first year of life to siblings and dogs may decrease the risk of subsequent egg allergy. Infants with a family history of allergy and those with parents born in East Asia are at increased risk of egg allergy.