Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trial.

Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%-68.2%), compared with 63.4% in the control group (95% CI 61.8%-65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%-20.7%), compared with 18.8% in the control group (95% CI 17.4%-20.2%) a difference of +0.6 percentage points (95% CI -1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Longitudinal peanut and Ara h 2 specific-IgE, -IgG4, and -IgG4/-IgE ratios are associated with the natural resolution of peanut allergy in childhood.

BACKGROUND: There are no studies of longitudinal immunoglobulin measurements in a population-based cohort alongside challenge-confirmed peanut allergy outcomes. Little is known about biomarkers for identifying naturally resolving peanut allergy during childhood. OBJECTIVES: To measure longitudinal trends in whole peanut and component Ara h 2 sIgE and sIgG4 in the first 10 years of life, in a population cohort of children with challenge-confirmed peanut allergy, and to determine whether peanut-specific immunoglobulin levels or trends are associated with peanut allergy persistence or resolution by 10 years of age. METHODS: One-year-old infants with challenge-confirmed peanut allergy (n = 156) from the HealthNuts study (n = 5276) were prospectively followed at ages 4, 6, and 10 years with questionnaires, skin prick tests, oral food challenges, and plasma total-IgE, sIgE and sIgG4 to peanut and Ara h 2. RESULTS: Peanut allergy resolved in 33.9% (95% CI = 25.3%, 43.3%) of children by 10 years old with most resolving (97.4%, 95% CI = 86.5%, 99.9%) by 6 years old. Decreasing Ara h 2 sIgE (p = .01) and increasing peanut sIgG4 (p < .001), Ara h 2 sIgG4 (p = .01), peanut sIgG4/sIgE (p < .001) and Ara h 2 sIgG4/sIgE (p < .001) from 1 to 10 years of age were associated with peanut allergy resolution. Peanut sIgE measured at 1 year old had the greatest prognostic value (AUC = 0.75 [95% CI = 0.66, 0.82]); however, no single threshold produced both high sensitivity and specificity. CONCLUSION: One third of infant peanut allergy resolved by 10 years of age. Decreasing sIgE and sIgG4 to peanut and Ara h 2 over time were associated with natural resolution of peanut allergy. However, biomarker levels at diagnosis were not strongly associated with the natural history of peanut allergy.

The Prevalence of IgE-Mediated Food Allergy and Other Allergic Diseases in the First 10 Years: The Population-Based, Longitudinal HealthNuts Study.

BACKGROUND: There are limited longitudinal data on the population prevalence of allergic conditions during childhood, and few studies have incorporated the reference standard oral food challenge to confirm food allergy. OBJECTIVE: To describe the population prevalence of IgE-mediated food allergy, eczema, asthma, and rhinitis at ages 6 and 10 years in Melbourne, Australia. METHODS: The HealthNuts study recruited 5,276 1-year-old infants in Melbourne, Australia, with repeat assessments at ages 6 and 10 years. At ages 6 and 10 years, carers completed a questionnaire on symptoms and doctor diagnosis of allergic conditions (International Study of Asthma and Allergies in Children). Children were invited to attend a clinic assessment including skin prick test, lung function tests, and oral food challenges when indicated. To minimize the impact of attrition bias, prevalence estimates among participants at ages 6 and 10 years were weighted to reflect characteristics of the whole cohort at recruitment. RESULTS: In total, 4,455 and 4,065 families participated at ages 6 and 10 years, respectively (84% and 77% of the original cohort). Of those, 73% and 55% of participants ages 6 and 10 years, respectively, completed clinical assessments. Overall, 36.5% (95% CI, 34.8-38.2) and 38.2% (95% CI, 36.5-40.1%) of 6- and 10-year-olds had at least one current allergic disease, and around one third of those had two or more allergic diseases. Food allergy occurred in 6.4% (95% CI, 5.6-7.2) of 6-year olds and 6.3% (95% CI, 5.5-7.2) of 10-year-olds. Among infants with challenge-confirmed food allergy in infancy, 45% had persistent disease at age 10 years. The prevalence of current diagnosed asthma at ages 6 and 10 years were 12.1% (95% CI, 10.9-13.3) and 13.1% (95% CI, 11.9-14.4), respectively, current eczema decreased slightly from 15.3% (95% CI, 14.1-19.7) at age 6 years to 12.9% (95% CI, 11.7-14.2) at age 10 years, and current rhinitis increased from 15.1% (95% CI, 13.9-16.5) at age 6 years to 25.0% (95% CI, 23.4-26.7) at age 10 years. CONCLUSIONS: Allergic diseases affect 40% of primary school-age children; one third have multiple allergic diagnoses. Challenge-confirmed food allergy prevalence remains high, and 45% of infants with food allergy have persistent disease to age 10 years.

The Human Health Impacts of the Red Imported Fire Ant in the Western Pacific Region Context: A Narrative Review.

Background: The red imported fire ant (RIFA) is one of the world's most destructive invasive species. RIFA stings are painful and can lead to allergic reactions, including life-threatening anaphylaxis, yet health impacts remain inadequately defined. Methods: We searched MEDLINE (Ovid) and Google Scholar (grey literature) from inception until 20 September 2023 for articles in English using search terms related to red imported fire ants and allergies, including anaphylaxis. Results: Approximately a third of the population in RIFA-infested areas are stung each year. The most frequent reaction is a sterile 1-2 mm pseudo pustule on the skin. Approximately 20% of stings cause a large local reaction and between about 0.5% and 2% stings cause a systemic allergic reaction which can range from skin symptoms to life-threatening anaphylaxis. Local biodiversity is also significantly disrupted by invading RIFA and may lead to complex adverse effects on human health, from agriculture losses to expanded ranges for pathogen vectors. Conclusions: The potential for red imported fire ants to establish themselves as an invasive species in the Western Pacific presents a substantial and costly health issue. Successful eradication and surveillance programs, to identify and eradicate new incursions, would avoid substantial health impacts and costs.

Specific and off-target immune responses following COVID-19 vaccination with ChAdOx1-S and BNT162b2 vaccines-an exploratory sub-study of the BRACE trial.

BACKGROUND: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. METHODS: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. FINDINGS: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. INTERPRETATION: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. FUNDING: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children's. BRACE trial funding is detailed in acknowledgements.

A genome catalog of the early-life human skin microbiome.

BACKGROUND: Metagenome-assembled genomes have greatly expanded the reference genomes for skin microbiome. However, the current reference genomes are largely based on samples from adults in North America and lack representation from infants and individuals from other continents. RESULTS: Here we use deep shotgun metagenomic sequencing to profile the skin microbiota of 215 infants at age 2-3 months and 12 months who are part of the VITALITY trial in Australia as well as 67 maternally matched samples. Based on the infant samples, we present the Early-Life Skin Genomes (ELSG) catalog, comprising 9483 prokaryotic genomes from 1056 species, 206 fungal genomes from 13 species, and 39 eukaryotic viral sequences. This genome catalog substantially expands the diversity of species previously known to comprise human skin microbiome and improves the classification rate of sequenced data by 21%. The protein catalog derived from these genomes provides insights into the functional elements such as defense mechanisms that distinguish early-life skin microbiome. We also find evidence for microbial sharing at the community, bacterial species, and strain levels between mothers and infants. CONCLUSIONS: Overall, the ELSG catalog uncovers the skin microbiome of a previously underrepresented age group and population and provides a comprehensive view of human skin microbiome diversity, function, and development in early life.

EAACI guidelines on the diagnosis of IgE-mediated food allergy.

This European Academy of Allergy and Clinical Immunology guideline provides recommendations for diagnosing IgE-mediated food allergy and was developed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Food allergy diagnosis starts with an allergy-focused clinical history followed by tests to determine IgE sensitization, such as serum allergen-specific IgE (sIgE) and skin prick test (SPT), and the basophil activation test (BAT), if available. Evidence for IgE sensitization should be sought for any suspected foods. The diagnosis of allergy to some foods, such as peanut and cashew nut, is well supported by SPT and serum sIgE, whereas there are less data and the performance of these tests is poorer for other foods, such as wheat and soya. The measurement of sIgE to allergen components such as Ara h 2 from peanut, Cor a 14 from hazelnut and Ana o 3 from cashew can be useful to further support the diagnosis, especially in pollen-sensitized individuals. BAT to peanut and sesame can be used additionally. The reference standard for food allergy diagnosis is the oral food challenge (OFC). OFC should be performed in equivocal cases. For practical reasons, open challenges are suitable in most cases. Reassessment of food allergic children with allergy tests and/or OFCs periodically over time will enable reintroduction of food into the diet in the case of spontaneous acquisition of oral tolerance.

BNT162b2 COVID-19 vaccination in children alters cytokine responses to heterologous pathogens and Toll-like receptor agonists.

Background: Vaccines can have beneficial off-target (heterologous) effects that alter immune responses to, and protect against, unrelated infections. The heterologous effects of COVID-19 vaccines have not been investigated in children. Aim: To investigate heterologous and specific immunological effects of BNT162b2 COVID-19 vaccination in children. Methods: A whole blood stimulation assay was used to investigate in vitro cytokine responses to heterologous stimulants (killed pathogens, Toll-like receptor ligands) and SARS-CoV-2 antigens. Samples from 29 children, aged 5-11 years, before and 28 days after a second BNT162b2 vaccination were analysed (V2 + 28). Samples from eight children were analysed six months after BNT162b2 vaccination. Results: At V2 + 28, interferon-γ and monocyte chemoattractant protein-1 responses to S. aureus, E. coli, L. monocytogenes, BCG vaccine, H. influenzae, hepatitis B antigen, poly(I:C) and R848 stimulations were decreased compared to pre-vaccination. For most of these heterologous stimulants, IL-6, IL-15 and IL-17 responses were also decreased. There were sustained decreases in cytokine responses to viral, but not bacterial, stimulants six months after BNT162b2 vaccination. Cytokine responses to irradiated SARS-CoV-2, and spike glycoprotein subunits (S1 and S2) were increased at V2 + 28 for most cytokines and remained higher than pre-vaccination responses 6 months after BNT162b2 vaccination for irradiated SARS-CoV-2 and S1. There was no correlation between BNT162b2 vaccination-induced anti-SARS-CoV2-receptor binding domain IgG antibody titre at V2 + 28 and cytokine responses. Conclusions: BNT162b2 vaccination in children alters cytokine responses to heterologous stimulants, particularly one month after vaccination. This study is the first to report the immunological heterologous effects of COVID-19 vaccination in children.

Bacillus Calmette-Guérin vaccination for protection against recurrent herpes labialis: a nested randomised controlled trial.

Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2-8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27-2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32-0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69-3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26-0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3-2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, and individual donors.

A genome catalog of the early-life human skin microbiome.

Metagenome-assembled genomes have greatly expanded the reference genomes for skin microbiome. However, the current reference genomes are largely based on samples from adults in North America and lack representation from infants and individuals from other continents. Here we used ultra-deep shotgun metagenomic sequencing to profile the skin microbiota of 215 infants at age 2-3 months and 12 months who were part of the VITALITY trial in Australia as well as 67 maternally-matched samples. Based on the infant samples, we present the Early-Life Skin Genomes (ELSG) catalog, comprising 9,194 bacterial genomes from 1,029 species, 206 fungal genomes from 13 species, and 39 eukaryotic viral sequences. This genome catalog substantially expands the diversity of species previously known to comprise human skin microbiome and improves the classification rate of sequenced data by 25%. The protein catalog derived from these genomes provides insights into the functional elements such as defense mechanisms that distinguish early-life skin microbiome. We also found evidence for vertical transmission at the microbial community, individual skin bacterial species and strain levels between mothers and infants. Overall, the ELSG catalog uncovers the skin microbiome of a previously underrepresented age group and population and provides a comprehensive view of human skin microbiome diversity, function, and transmission in early life.

Infant food allergy phenotypes and association with lung function deficits and asthma at age 6 years: a population-based, prospective cohort study in Australia.

BACKGROUND: Food allergy is considered a precursor to asthma in the context of the atopic march, but the relationship between infant food allergy phenotypes and lung function and asthma in childhood is unclear. We aimed to examine the association between food sensitisation and challenge-confirmed food allergy in infancy, as well as persistent and resolved food allergy up to age 6 years, and the risk of lung function deficits and asthma at age 6 years. METHODS: The longitudinal, population-based HealthNuts cohort study in Melbourne, VIC, Australia, recruited 5276 infants children aged 1 year who attended council-run immunisation sessions between Sept 28, 2007, and Aug 5, 2011. At age 1 year, all children completed skin prick testing to four food allergens (egg, peanut, sesame, and either shrimp or cow's milk) and an oral food challenge (egg, peanut, and sesame) at the Royal Children's Hospital in Melbourne. Parents completed questionnaires about their infant's allergy history, demographic characteristics, and environmental exposures. At age 6 years, children were invited for a health assessment that included skin prick testing for ten foods (milk, egg, peanut, wheat, sesame, soy, shrimp, cashew, almond, and hazelnut) and eight aeroallergens (alternaria, cladasporum, house dust mite, cat hair, dog hair, bermuda grass, rye grass, and birch mix), oral food challenges, and lung function testing by spirometry. Questionnaires completed by parents (different to those completed at age 1 year) captured the child's allergy and respiratory history and demographics. We investigated associations between food allergy phenotypes (food-sensitised tolerance or food allergy; and ever, transient, persistent, or late-onset food allergy), lung function spirometry measures (forced expiratory volume in 1 sec [FEV1] and forced vital capacity [FVC] z-scores, FEV1/FVC ratio, forced expiratory flow at 25% and 75% of the pulmonary volume [FEF25-75%], and bronchodilator responsiveness), and asthma using regression methods. Only children with complete data on the exposure, outcome, and confounders were included in models. Infants without food sensitisation or food allergy at age 1 year and 6 years served as the reference group. FINDINGS: Of 5276 participants, 3233 completed the health assessment at age 6 years and were included in this analysis. Food allergy, but not food-sensitised tolerance, at age 1 year was associated with reduced FEV1 and FVC (aß -0·19 [95% CI -0·32 to -0·06] and -0·17 [-0·31 to -0·04], respectively) at age 6 years. Transient egg allergy was associated with reduced FEV1 and FVC compared with never having egg allergy (-0·18 [95% CI -0·33 to -0·03] and -0·15 [-0·31 to 0·00], respectively), whereas persistent egg allergy was not (FEV1 -0·09 [-0·48 to 0·31]; FVC -0·20 [-0·62 to 0·21]). Transient peanut allergy was associated with reduced FEV1 and FVC (FEV1 aß -0·37 [-0·79 to 0·04] and FVC aß -0·55 [-0·98 to -0·12]), in addition to persistent peanut allergy (FEV1 aß -0·30 [-0·54 to -0·06] and FVC aß-0·30 [-0·55 to -0·05]), and late-onset peanut allergy (FEV1 aß -0·62 [-1·06 to -0·18] and FVC aß-0·49 [-0·96 to -0·03]). Estimates suggested that food-sensitised tolerance and food allergy were associated with reduced FEF25-75%, although some estimates were imprecise. Food allergy phenotypes were not associated with an FEV1/FVC ratio. Late-onset peanut allergy was the only allergy phenotype that was possibly associated with increased risk of bronchodilator responsiveness (2·95 [95% CI 0·77 to 11·38]). 430 (13·7%) of 3135 children were diagnosed with asthma before age 6 years (95% CI 12·5-15·0). Both food-sensitised tolerance and food allergy at age 1 year were associated with increased asthma risk at age 6 years (adjusted odds ratio 1·97 [95% CI 1·23 to 3·15] and 3·69 [2·81 to 4·85], respectively). Persistent and late-onset peanut allergy were associated with higher asthma risk (3·87 [2·39 to 6·26] and 5·06 [2·15 to 11·90], respectively). INTERPRETATION: Food allergy in infancy, whether it resolves or not, is associated with lung function deficits and asthma at age 6 years. Follow-up studies of interventions to prevent food allergy present an opportunity to examine whether preventing these food allergies improves respiratory health. FUNDING: National Health & Medical Research Council of Australia, Ilhan Food Allergy Foundation, AnaphylaxiStop, the Charles and Sylvia Viertel Medical Research Foundation, the Victorian Government's Operational Infrastructure Support Program.

Efficacy and safety of oral immunotherapy for peanut, cow's milk, and hen's egg allergy: A systematic review of randomized controlled trials.

BACKGROUND: Oral immunotherapy (OIT) is a promising treatment for food allergies; however, safety is a concern. We synthesized evidence from the best randomized controlled trials (RCTs) on efficacy/safety of OIT for desensitization (DS) and remission (sustained unresponsiveness (SU)) in IgE mediated allergy to peanut, hen's eggs, and cow's milk. BODY: We searched Pubmed, EMBASE, and Cochrane databases (Until Oct 22) identifying 16 eligible RCTs published in English measuring food allergy by food challenge at the beginning and at the end of the study. The Cochrane Risk of Bias tool was used to assess study quality. We found 18 eligible studies. There was evidence of efficacy for DS for all allergens: peanut (RR 11.32; 95% CI 5.93, 21.60, I2 49%, 8 studies); hen's egg (RR 4.67; 2.66, 8.21, I2 0%, 5 studies); cow's milk (RR 13.98; 3.51, 55.65, I2 0%, 4 studies) and evidence for SU for peanut (RR 7.74; 2.90, 20.69, I2 0%, 3 studies) and hen's egg (RR 6.91; 1.67, 28.57, I2 0%, 2 studies). Allergic events were increased with intervention, and risk of adrenaline use increased for peanut RR 2.96; 1.63, 5.35, I2 0%, 8 studies; egg RR 1.71; 0.42, 6.92, I2 0%, 6 studies; and milk RR 8.45; 2.02, 35.27, I2 0%, 4 studies. CONCLUSION: We found strong evidence that peanut, hen's egg, and cow's milk OIT can induce DS and some evidence for remission. There was a high risk of allergic reactions. Generalizability to the entire food allergic population is not known.

Cashew Allergy Prevalence and Sensitization in 1-Year-Old Infants.

BACKGROUND: Cashew allergy is the most common tree nut allergy in Australia, but there are limited data on the population-level prevalence and risk factors. OBJECTIVE: Describe the prevalence of cashew sensitization and allergy in 12-month-old infants and identify risk factors. METHODS: Data were from the EarlyNuts cohort, a population-based sample of infants recruited in Melbourne, Australia. Families completed a questionnaire and infants underwent a skin prick test (SPT) to cashew. Infants with positive SPTs were offered food challenges. Questionnaires collected demographic data and allergy risk factors. Allergy outcomes were determined by challenge outcomes or a convincing history of an allergic reaction. We used weights to adjust estimated prevalence to reflect the distribution of risk factors among the combined sample of participants and nonparticipants. RESULTS: We recruited 1,933 participants and identified 1,414 cashew allergy outcomes. Of these, 1.96% (95% CI, 1.28-2.99) had an SPT result of 3 mm or greater and 1.49% (95% CI, 0.91-2.44) were allergic to cashew. Infants with eczema or peanut allergy in the first year of life were more likely to be allergic to cashew (adjusted odds ratio = 5.75; 95% CI, 2.08-15.88; P = .001; and adjusted odds ratio = 19.30; 95% CI, 5.44-68.43; P < .001, respectively). Twenty-five percent of participants had cashew introduced before 12 months (95% CI, 22.7-27.8). There was no association between the timing of cashew introduction and cashew allergy. CONCLUSIONS: To our knowledge, this is the first study describing the prevalence of and risk factors for cashew allergy in a population-based infant cohort. Eczema and peanut allergy were associated with an increased risk of cashew allergy. Few infants were introduced to cashew before age 12 months, which suggests that infant feeding guidelines have not yet translated to the earlier introduction of all allergens.

Australian Infant Food Allergy Emergency Presentations Following Updated Early Food Introduction Guidelines.

BACKGROUND: The Australasian Society of Clinical Immunology and Allergy food allergy prevention guidelines were updated in 2016 to recommend home introduction of allergenic foods actively in the first year of life, including to infants at high risk of allergy. An important consideration for parents and providers is whether this practice increases food allergy reactions or anaphylaxis. OBJECTIVE: We aimed to determine whether the 2016 update of food allergy prevention guidelines was associated with an increase in food allergy or anaphylaxis emergency department (ED) presentations. METHODS: We obtained hospital electronic medical records for infants aged 4 to 12 months who attended the Royal Children's Hospital Melbourne ED in 2015 or in 2018 with a presenting problem or an encounter diagnosis of food allergy or anaphylaxis. RESULTS: Emergency department presentations owing to food allergy increased from 1.0% (95% CI, 0.85-1.23) in 2015 to 1.4% (95% CI, 1.22-1.67) in 2018 (P = .006). There was no increase in the number of anaphylaxis presentations (28 in 2015 and 22 in 2018) or peanut anaphylaxis presentations (three in 2015 and three in 2018). Overall, the proportion of food allergy presentations attributed to IgE-mediated food allergy was similar (82.1% in 2015 and 84.1% in 2018), whereas peanut allergy presentations increased slightly, although not statically significantly, from 14.6% to 21.2% (P = .09). Food protein-induced enterocolitis syndrome ED presentations were five in 2015 (4.3%) and 12 in 2018(7.6%), although not statistically significant (P = .25). CONCLUSIONS: Changes to food allergy prevention guidelines recommending the earlier introduction of allergenic food may have led to a small increase in ED presentations for food allergy but not anaphylaxis.

Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy.

BACKGROUND: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. METHODS: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. RESULTS: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. CONCLUSIONS: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.).

Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

TreEAT trial: Protocol for a randomized controlled trial investigating the efficacy and safety of early introduction of tree nuts for the prevention of tree nut allergy in infants with peanut allergy.

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 with 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, randomized, controlled trial (RCT). Infants (n = 212) aged 4-11 months with peanut allergy will be randomized 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 18 months, with questionnaires and SPT to peanut and tree nuts. Peanut and tree nut OFCs will be performed as required to determine the 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 randomization 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.