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The last decade has seen an unprecedented pace of change, particularly of clinical research in atopic dermatitis (AD). This review summarizes some key discoveries. Over the last 10 years, nearly half of all studies investigated the efficacy and safety of novel therapeutic agents, particularly biologics and small molecules. Clear demonstration of benefit in clinical trials with no significant safety concerns provided strong evidence leading to subsequent Food and Drug Administration approval and routine use of the anti-IL-4 receptor alpha antagonist dupilumab in patients 6 months and older, the selective Janus kinase 1 (JAK1) inhibitors upadacitinib for patients 12 years and older and abrocitinib, the IL-13 antagonist tralokinumab, and the JAK1/2 inhibitor baricitinib for adults 18 years and older. Several other drugs are in the pipeline. Other areas under the spotlight have been trials of skin moisturizers and probiotics in the prevention of AD, investigating the role of filaggrin and skin barrier function and the role of skin and gut microbiome, with Staphylococcus aureus second immunoglobulin-binding protein having been found to uniquely trigger allergic skin responses in AD. Skin microbiome, epidermal metabolites/structural components, and local inflammatory biomarkers are now commonly assessed using genomic and proteomic analysis of tape strips rather than more invasive biopsy to identify factors such as C-C motif chemokine ligand-17 that correlate with disease severity and response to therapy. Overall, the last decade has ushered in a new and exciting era in our understanding, diagnosis, and treatment of this common allergic skin disease.

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

The prevalence of food allergy (FA) is increasing in some areas of the globe, highlighting the need for better strategies for prevention, diagnosis, and therapy. In the last few decades, we have made great strides in understanding the causes and mechanisms underlying FAs, prompting guideline updates. Earlier guidelines recommended avoidance of common food allergens during pregnancy and lactation and delaying the introduction of allergenic foods in children aged between 1 and 3 years. Recent guidelines for allergy prevention recommend consumption of a healthy and diverse diet without eliminating or increasing the consumption of allergenic foods during pregnancy or breast-feeding. Early introduction of allergenic foods is recommended by most guidelines for allergy prevention after a period of exclusive breast-feedng (6 months [World Health Organization] or 4 months [European Academy of Allergy and Clinical Immunology]). New diagnostics for FA have been developed with varied availability of these tests in different countries. Finally, the first oral immunotherapy drug for FA was approved by the US Food and Drug Administration and European Medicines Agency in 2020. In this review, we will address the global prevalence of FA, our current understanding of the causes of FA, and the latest guidelines for preventing, diagnosing, and treating FA. We will also discuss similarities and differences between FA guidelines.

IgE-mediated food allergies have been linked to suboptimal naïve CD4 T (nCD4T) cell activation in infancy, underlined by epigenetic and transcriptomic variation. Similar attenuated nCD4T cell activation in adolescents with food allergy have also been reported, but these are yet to be linked to specific epigenetic or transcriptional changes.We generated genome-wide DNA methylation data in purified nCD4 T cells at quiescence and following activation in a cohort of adolescents (aged 10-15 years old) with peanut allergy (peanut only or peanut + ≥1 additional food allergy) (FA, n = 29), and age-matched non-food allergic controls (NA, n = 18). Additionally, we assessed transcriptome-wide gene expression and cytokine production in these cells following activation.We found widespread changes in DNA methylation in both NA and FA nCD4T cells in response to activation, associated with the T cell receptor signaling pathway. Adolescents with FA exhibit unique DNA methylation signatures at quiescence and post-activation at key genes involved in Th1/Th2 differentiation (RUNX3, RXRA, NFKB1A, IL4R), including a differentially methylated region (DMR) at the TNFRSF6B promoter, linked to Th1 proliferation. Combined analysis of DNA methylation, transcriptomic data and cytokine output in the same samples identified an attenuated interferon response in nCD4T cells from FA individuals following activation, with decreased expression of several interferon genes, including IFN-γ and a DMR at a key downstream gene, BST2.We find that attenuated nCD4T cell responses from adolescents with food allergy are associated with specific epigenetic variation, including disruption of interferon responses, indicating dysregulation of key immune pathways that may contribute to a persistent FA phenotype. However, we recognize the small sample size, and the consequent restraint on reporting adjusted p-value statistics as limitations of the study. Further study is required to validate these findings.

Early introduction of allergenic foods into an infant's diet is currently the most promising strategy to prevent food allergy, with infant guidelines around the world shifting from promoting avoidance to actively encourage the introduction of allergenic foods in the infant diet. Infant feeding guidelines vary according to regional public health priorities, and knowledge gaps remain, resulting in ongoing challenges for clinicians and families to translate guidelines into practical strategies for the introduction of complementary foods for food allergy prevention. Evidence from Australia demonstrates high community support and uptake of revised guidelines with most parents introducing allergenic foods in the first year of life, although this has not had the expected impact on substantially reducing food allergy prevalence. To uptake of guidelines from other countries is less clear, and several barriers have been noted in infant feeding RCTs, which may warrant intervention strategies. Further research is needed to understand additional strategies for food allergy prevention, particularly in infants who develop food allergy prior to when they are developmentally ready to commence solids. Several RCTs are underway investigating preventative strategies that target the window before allergen ingestion, such as vitamin D supplementation, emollient use, and immunizations that prime the immune response away from a Th2-driven allergic phenotype. Further research is also needed to understand the role of the environment and the host environment in the development of tolerance to foods.

In the absence of a clear clinical history of reaction, diagnosis of cashew allergy using skin prick tests (SPT) or cashew-specific IgE requires a high number of oral food challenges (OFC). By using Ana o 3 sIgE alone, or a two-step diagnostic algorithm using cashew sIgE followed by Ana o 3 sIgE, there is a reduced need for OFC. We aimed to perform a cost comparison for both of these approaches compared with cashew SPT alone.Pooled individual-level data from 6 studies were used to determine diagnostic accuracy and OFC rate. Two studies used cashew SPT (n = 567, 198 allergic), with 95% positive and negative predictive values of ≥12 mm and3 mm. Four studies were included in the pathways for Ana o 3 sIgE alone or a 2-step algorithm incorporating cashew and Ana o 3 sIgE (n = 271, 156 allergic). Cut-offs used were ≥8.5kUA/L and ≤0.1kUA/L for cashew sIgE and ≥0.35kUA/L and ≤0.1kUA/L for Ana o 3 sIgE. Costs were constructed based on unit prices from hospital inpatient admissions, expenses incurred by families, individual patient data on allergic reaction types and rates, and adrenaline autoinjector carriage, applying a health system perspective.Modeled data through the Ana o 3 pathway resulted in a 46.43% cost reduction (€307,406/1000 patients) compared with using cashew SPT alone (€573,854/1000 patients). The 2-step algorithm resulted in a 44.94% cost reduction compared with SPT alone (€315,952.82/1000 patients). Both the Ana o 3 pathway and 2-step algorithm resulted in a 79%-80% reduction in OFCs compared with SPT.Using Ana o 3 as a standalone test for cashew allergy diagnosis or a 2-step algorithm incorporating cashew sIgE and Ana o 3 sIgE is accurate and results in a large reduction in both OFCs and health system costs compared with cashew SPT alone.

Background and objective As the rise in prevalence of allergic diseases worldwide corresponds in time with increasing infant vaccination, it has been hypothesized that childhood vaccination may increase the risk of allergic disease. We aimed to synthesize the literature on the association between childhood vaccination and allergy. Design We searched the electronic databases PubMed and EMBASE (January 1946-January 2018) using vaccination and allergy terms. Methods Two authors selected papers according to the inclusion criteria. Pooled effects across studies were estimated using random-effects meta-analysis. Due to inadequate number of homogeneous publications on newer and underused vaccines, meta-analysis was limited to allergic outcomes following administration of (Bacillus Calmette-Guerin) BCG, measles or pertussis vaccination. The review was prospectively registered in the PROSPERO systematic review registry (NO: CRD42017071009). Results A total of 35 publications based on cohort studies and 7 publications based on randomized controlled trials (RCTs) met the inclusion criteria. RCTs: From 2 studies, early vaccination with BCG vaccine was associated with a reduced risk of eczema (RR = 0.83; 95% CI = 0.73-0.93; I2 = 0%) but not food allergy or asthma. No association was found between pertussis vaccine and any allergic outcome based on a single RCT. Cohort studies Childhood measles vaccination was associated with a reduced risk of eczema (RR = 0.65; 95% CI = 0.47-0.90, I2 = 0.0%), asthma (RR = 0.78; 95% CI = 0.62-0.98, I2 = 93.9%) and, with a similar, statistically non-significant reduction in sensitization (RR = 0.78; 95% CI = 0.61-1.01, I2 = 19.4%). Conclusions We found no evidence that childhood vaccination with commonly administered vaccines was associated with increased risk of later allergic disease. Our results from pooled analysis of both RCTs and cohort studies suggest that vaccination with BCG and measles vaccines were associated with a reduced risk of eczema.

While the relationship between pollen and respiratory allergies is well-documented, the role of short-term pollen exposure in food allergy and eczema flares has not previously been explored. We aimed to investigate these associations in a population-based sample of children.We investigated 1- (n = 1108) and 6-year-old (n = 675) children in the grass pollen season from the HealthNuts cohort. Grass pollen concentrations were considered on the day of testing (lag 0), up to three days before (lag 1-lag 3) and cumulatively (lag 0-3). Associations between grass pollen and food skin-prick test reactivity (SPT ≥ 2 mm at age 1 year and ≥ 3 mm at age 6 years), eczema flares, challenge-confirmed food allergy, reaction threshold to oral food challenges (OFC), and serum food-specific IgE levels were analyzed using either logistic or quantile regression models. Atopy and family history of allergic disease were considered as potent effect modifiers.Grass pollen at lag 0-3 (every 20 grains/msup3/supincrease) was associated with an up to 1.2-fold increased odds of food SPT reactivity and eczema flares in 6-year-olds. In 1-year-olds, the associations were only observed for peanut in those with a family history of food allergy. Increasing grass pollen concentrations were associated with a lower reaction threshold to OFC and higher serum IgE levels in peanut-allergic 1-year-olds only.Increasing grass pollen concentration was associated with increased risk of food SPT reactivity and eczema flares in children. The associations in peanut-allergic infants may be related to immune activation and/or peanut and grass pollen cross-reactivity leading to a lower reaction threshold.

BackgroundThere is significant overdiagnosis of milk allergy in young children in some countries, leading to unnecessary use of specialized formula. This guidance, developed by experts without commercial ties to the formula industry, aims to reduce milk allergy overdiagnosis and support carers of children with suspected milk allergy.MethodsDelphi study involving two rounds of anonymous consensus building and an open meeting between January and July 2021. Seventeen experts in general practice, nutrition, midwifery, health visiting, lactation support and relevant areas of paediatrics participated, located in Europe, North America, Middle East, Africa, Australia and Asia. Five authors of previous milk allergy guidelines and seven parents provided feedback.FindingsParticipants agreed on 38 essential recommendations through consensus. Recommendations highlighted the importance of reproducibility and specificity for diagnosing milk allergy in children with acute or delayed symptoms temporally related to milk protein ingestion; and distinguished between children directly consuming milk protein and exclusively breastfed infants. Consensus was reached that maternal dietary restriction is not usually necessary to manage milk allergy, and that for exclusively breastfed infants with chronic symptoms, milk allergy diagnosis should only be considered in specific, rare circumstances. Consensus was reached that milk allergy diagnosis does not need to be considered for stool changes, aversive feeding or occasional spots of blood in stool, if there is no temporal relationship with milk protein ingestion. When compared with previous guidelines, these consensus recommendations resulted in more restrictive criteria for detecting milk allergy and a more limited role for maternal dietary exclusions and specialized formula.InterpretationThese new milk allergy recommendations from non-conflicted, multidisciplinary experts advise narrower criteria, more prominent support for breastfeeding and less use of specialized formula, compared with current guidelines.

Food allergy is a major public health issue with growing prevalence in the urbanized world and significant impact on the lives of allergic patients and their families. Research into the risk factors that have contributed to this increase and their underlying immune mechanisms could lead us to definitive ways for treatment and prevention of food allergy. For the time being, introduction of peanut and other allergenic foods in the diet at the time of weaning seems to be an effective way to prevent the development of food allergy. Improved diagnosis and appropriate management and support of food allergic patients are central to patient care with food immunotherapy and biologics making the transition to clinical practice. With the new available treatments, it is becoming increasingly important to include patients' and family preferences to provide a management plan tailored to their needs.

Background Few studies have investigated adverse food reactions among food-allergic children in a population-based sample, which is critical for the development of evidence-based management strategies. Objective We aimed to evaluate the frequency, characteristics, and risk factors for adverse food reactions, including anaphylaxis, among food-allergic 6-year-old-children using the population-based HealthNuts study. Methods The HealthNuts study of 5276 infants (1-year-old) followed them up at age 6 years (84.4% participated). A total of 260 children with IgE-mediated food allergy who completed a questionnaire detailing recent adverse food reactions were included in this analysis. Results Among food-allergic children, 44.6% (95% CI, 38.6%-50.8%) reported an adverse food reaction in the last 12 months and 10.8% (95% CI, 7.5%-15.2%) reported an anaphylactic reaction, although only half of these were recognized as anaphylaxis by parents. Adrenaline autoinjectors were used in 25% (4 of 16) of recognized anaphylaxis episodes. Nut allergy was associated with a reduced risk of having an adverse reaction (adjusted odds ratio, 0.3; 95% CI, 0.1-0.7). There were trends that adverse reactions were more likely in children with at least 1 parent born in Asia compared with both parents born in Australia (adjusted odds ratio, 1.9; 95% CI, 0.9-3.9), and in children with 3 or more food allergies compared with children with a single food allergy (adjusted odds ratio, 1.8; 95% CI, 0.9-3.5). Conclusions Adverse food reactions occurred in almost half of all food-allergic 6-year-old children and anaphylaxis occurred in 1 in 10 children over a 12-month period. Anaphylaxis was poorly recognized and adrenaline autoinjectors were not used appropriately. Improved regular education on the prevention, recognition, and management of adverse food reactions is urgently needed.

While exposure to environmental greenness in childhood has shown mixed associations with the development of allergic disease, the relationship with food allergy has not been explored. We investigated the association between exposure to environmental greenness and challenge-confirmed food allergy in a large population-based cohort.The HealthNuts study recruited 5276 12-month-old infants in Melbourne, Australia, who underwent skin prick testing to peanut, egg, and sesame; infants with a detectable wheal underwent food challenges to determine food allergy status. Environmental greenness was estimated using the normalized difference vegetation index (NDVI) for five buffer zones around the infant's home address: at the home, 100 m, 500 m, 800 m, and 1600 m radial distances. Environmental greenness was categorized into 3 tertiles and mixed effects logistic regression models quantified the association between greenness and the risk of food allergy, adjusting for confounding and accounting for clustering at the neighborhood level.NDVI data were available for n = 5097. For most buffer zones, medium and high greenness, compared to low greenness, was associated with an increased risk of peanut allergy (eg, 100 m tertile 2 aOR 1.89 95% CI 1.22-2.95, tertile 3 aOR 1.78 95% CI 1.13-2.82). For egg allergy, the effect sizes were smaller (100 m tertile 2 aOR 1.52 95% CI 1.16-1.97, tertile 3 aOR 1.38 95% CI 1.05-1.82). Socioeconomic status (SES) modified the association between greenness and peanut allergy, but not egg allergy; associations were apparent in the low SES group but not in the high SES group (p for interaction 0.08 at 100 m). Air pollution (PM2.5) also modified the associations between environmental greenness and food allergy, with associations present in high air pollution areas but not low (p for interaction at 100 m 0.05 for peanut and 0.06 for egg allergy.) CONCLUSION: Increased exposure to environmental greenness in the first year of life was associated with an increased risk of food allergy. Increased greenness may correlate with higher pollen levels which may trigger innate immune responses skewing the immune system to the Th2-dependent allergic phenotype; additionally, some pollen and food allergens are cross-reactive. Given the mixed data on greenness and other allergies, the relationship appears complex and may also be influenced by confounding variables outside those that were measured in this study.

Food-allergic consumers encounter inadequate, confusing, and ambiguous allergen information for packaged and unpackaged foods. Key Australian and New Zealand allergy organizations convened multiple forums to facilitate discussions among consumers, food manufacturers, food retailers, regulatory bodies, researchers, and health professionals to develop a unified approach to improving food allergen management. The following stakeholder consensus statement provides a foundation for advocacy for improved food allergen management and safety. It is the responsibility of consumers to: 1. declare their food allergies and read food labels (including ingredient lists and allergen declaration statements), and 2. ultimately make their own judgment about the foods they choose to consume. We consider that to enable consumers to make informed decisions about their safety, It is the responsibility of packaged food manufacturers to: 1. follow robust allergen management practices including quantitative risk assessment, and 2. use clear, consistent labeling to inform consumers about that food's allergen content, including the possible presence of unintended allergens. It is the responsibility of food service establishments and providers to: 1. follow robust allergen management practices, and 2. ensure that staff understand and can inform consumers about the allergen content of the food they provide, including the possible presence of unintended allergens.

Background: Food allergies are a significant public health issue, and the only effective management option currently available is strict avoidance of all foods containing the allergen. In view of the practical impossibility of limiting risks to zero, quantitative allergen risk assessment and management strategies are needed. Objective: We sought to develop appropriate methods for informing population-based risk assessments and risk management programs to benefit all stakeholders but particularly patients with food allergy. Methods: Individual thresholds for food allergens (maximum tolerable doses and minimum eliciting doses) can ideally be established through double-blind, placebo-controlled food challenges. If double-blind, placebo-controlled food challenge data are not available, data from widely used open food challenges using predefined objective criteria can also provide useful data regarding minimum eliciting doses. For more than 20 years, the Netherlands Organisation for Applied Scientific Research and the Food Allergy Research and Resource Program at the University of Nebraska-Lincoln have been collecting individual maximum tolerable doses and minimum eliciting doses that produce objective symptoms from published and unpublished clinical data to better refine knowledge regarding the sensitivity of the population to food allergens. Results: In this article we provide in-depth insights into the methodology applied by the Netherlands Organisation for Applied Scientific Research and Food Allergy Research and Resource Program to derive individual maximum tolerable doses and minimum eliciting doses for objective symptoms from clinical food challenge data. More than 90 examples for determining individual allergic thresholds are presented. Conclusion: With the methodology presented in this article, we aim to stimulate harmonization and transparency in quantitative food allergen risk assessment and risk management programs, encouraging their wider adoption. © 2019 American Academy of Allergy, Asthma & Immunology

Background The genetic determinants of food allergy have not been systematically reviewed. We therefore systematically reviewed the literature on the genetic basis of food allergy, identifying areas for further investigation. Methods We searched three electronic databases (MEDLINE, EMBASE and PubMed) on 9 January 2018. Two authors screened retrieved articles for review according to inclusion criteria and extracted relevant information on study characteristics and measures of association. Eligible studies included those that reported an unaffected nonatopic control group, had genetic information and were carried out in children. Results Of the 2088 studies retrieved, 32 met our inclusion criteria. Five were genome-wide association studies, and the remaining were candidate gene studies. Twenty-two of the studies were carried out in a predominantly Caucasian population with the remaining 10 from Asian-specific populations or unspecified ethnicity. We found FLG, HLA, IL10, IL13, as well as some evidence for other variants (SPINK5, SERPINB and C11orf30) that are associated with food allergy. Conclusions Little genetic research has been carried out in food allergy, with FLG, HLA and IL13 being the most reproducible genes for an association with food allergy. Despite promising results, existing genetic studies on food allergy are inundated with issues such as inadequate sample size and absence of multiple testing correction. Few included replication analyses or population stratification measures. Studies addressing these limitations along with functional studies are therefore needed to unravel the mechanisms of action of the identified genes.

Diagnosis of peanut allergy presents a significant clinical challenge. Accurate diagnosis is critical for patient management and prevention of allergic reactions, whereas overdiagnosis or failure to diagnose tolerance in a previously allergic patient can lead to unnecessary dietary restrictions and impaired quality of life. Oral food challenges, the criterion standard for diagnosis, pose a risk of potentially severe allergic reactions, and are time- and resource- intensive. In this article, we review other currently available tests for peanut allergy and present the strengths and weaknesses of each to assist the clinician in determining which test might be appropriate for their patients, as well as highlighting emerging tests currently in development. Traditional tests for peanut-specific IgE (skin prick testing and specific IgE) remain useful as first-line tests-a negative test result is useful for excluding peanut allergy and a high positive result has a high specificity for peanut allergy. For those with an intermediate positive test result, Ara h 2 testing might be useful as a second step. Basophil activation tests and peanut protein epitope-specific IgE analyses appear promising in recent studies; however, further research is required into standardization, validation, and cost-effectiveness. Given the limitations of existing tests for peanut allergy, there remains a clear need for improvement. Finding a safe and affordable method for peanut allergy diagnosis that is both sensitive and specific remains an active area of research.

Prospectively collected data on the natural history of food allergy are lacking.We examined the natural history of egg and peanut allergy in children from age 1 to 6 years and assessed whether a skin prick test (SPT) result or other clinical factors at diagnosis are associated with the persistence or resolution of food allergy in early childhood.The HealthNuts cohort consists of 5276 children who were recruited at age 1 year and have been followed prospectively. Children with food allergy at age 1 year (peanut [n = 156] or raw egg [n = 471] allergy ) and children who developed new sensitizations or food reactions after age 1 year were assessed for food sensitization and allergy (confirmed by oral food challenge when indicated) at the 6-year follow-up.New-onset food allergy developed by age 6 years was more common for peanut (0.7% [95% CI = 0.5%-1.1%]) than egg (0.09% [95% CI = 0.03%-0.3%]). Egg allergy resolved more commonly (89% [95% CI = 85%-92%]) than peanut allergy (29% [95% CI = 22%-38%]) by age 6 years. The overall weighted prevalence of peanut allergy at age 6 years was 3.1% (95% CI = 2.6-3.7%) and that of egg allergy was 1.2% (95% = CI 0.9%-1.6%). The factors at age 1 year associated with persistence of peanut allergy were peanut SPT result of 8 mm or larger (odds ratio [OR] = 2.35 [95% CI 1.08-5.12]), sensitization to tree nuts (adjusted OR [aOR] = 2.51 [95% CI = 1.00-6.35]), and early-onset severe eczema (aOR = 3.23, [95% CI 1.17-8.88]). Factors at age 1 associated with persistence of egg allergy at age 6 were egg SPT result of 4 mm or larger (OR = 2.98 [95% CI 1.35-6.36]), other (peanut and/or sesame) food sensitizations (aOR = 2.80 [95% CI = 1.11-7.03]), baked egg allergy (aOR = 7.41 [95% CI = 2.16-25.3]), and early-onset severe eczema (aOR = 3.77 [95% CI = 1.35-10.52]).Most egg allergy and nearly one-third of peanut allergy resolves naturally by age 6 years. The prevalence of peanut allergy at age 6 years was similar to that observed at age 1 year, largely owing to new-onset food peanut allergy after age 1 year. Infants with early-onset eczema, larger SPT wheals, or multiple food sensitizations and/or allergies were less likely to acquire tolerance to either peanut or egg.

Grass pollen exposure is a risk factor for childhood asthma hospital attendances. However, its short-term influence on lung function, especially among those with other allergic conditions, has been less well-studied.To investigate this association in a population-based sample of children.Within the HealthNuts cohort, 641 children performed spirometry during the grass pollen season. Grass pollen concentration was considered on the day of testing (lag 0), up to 3 days before (lag 1-lag 3), and cumulatively (lag 0-3). We used linear regression to assess the relevant associations and examined potential interactions with current asthma, hay fever or eczema, and food allergy.Associations were observed only in children with allergic disease (P value for interaction ≤ 0.1). In children with food allergy, grass pollen concentration was associated with a lower ratio of forced expiratory volume in 1 second to forced vital capacity (FEVA proactive approach needs to be enforced to manage susceptible children, especially those with food allergy, before high-grass pollen days.

The association between mode of delivery and the risk of food allergy remains unclear due to the absence of studies with both challenge-proven food allergy outcomes and detailed information on the type of caesarean delivery.We assessed whether emergency or elective caesarean, or caesarean delivery in the presence or absence of labor initiation, is associated with the risk of food allergy.The HealthNuts study recruited 5276 12-month-old infants who underwent skin prick testing and oral food challenge to ascertain food allergy status, and linked the child's study data to additional birth data from the Victorian Perinatal Data Collection.Parents of 3006 children consented to data linkage, and birth data were obtained on 2045. In this subgroup, 30% were born by caesarean and 13% had food allergy. Caesarean delivery, compared with vaginal birth, was not associated with the risk of food allergy (adjusted odds ratio [aOR]: 0.95, 95% confidence interval [CI]: 0.70, 1.30). Neither caesarean delivery before the onset of labor, nor after the onset of labor, was associated with the risk of food allergy (aOR: 0.83, 95% CI: 0.55-1.23 and aOR: 1.13, 95% CI: 0.75-1.72, respectively). Delivery by elective or emergency caesarean, compared with vaginal delivery, was not associated with risk of food allergy (aOR: 1.05, 95% CI: 0.71-1.55 and aOR: 0.86, 95% CI: 0.56-1.31). There was no evidence of effect modification by breastfeeding, older siblings, pet dog ownership, or maternal allergy.Caesarean delivery, either with or without labor, or elective or emergency, was not associated with the risk of food allergy in a population-based cohort of 12-month-old infants.

Background Approximately 5% of adolescents have a food allergy, with peanut and tree nut allergies the most common. Having two or more food allergies in adolescence also doubles the risk of any adverse food reaction, and is associated with increased dietary and social burden. Investigations of immune function in persistently food allergic children are rare. Objective In the present study, we aimed to investigate the immune mechanisms that underlie food allergy in adolescence. Methods We used high-dimensional flow cytometry, unsupervised computational analysis and functional studies to comprehensively phenotype a range of non-antigen-specific immune parameters in a group of well-characterized adolescents with clinically defined single peanut allergy, multi-food allergy and aged-matched non-food allergic controls. Results We show that food allergic adolescents have higher circulating proportions of dendritic cells (p = .0084, FDR-adjusted p = .087, median in no FA: 0.63% live cells, in FA: 0.93%), and higher frequency of activated, memory-like Tregs relative to non-food allergic adolescents (p = .011, FDR-adjusted p = .087, median in no FA: 0.49% live cells, in FA: 0.65%). Cytokine profiling revealed that CD3/CD28 stimulated naive CD4 T cells from food allergic adolescents produced less IL-6 (p = .0020, FDR-adjusted p = .018, median log2 fold change [stimulated/unstimulated] in no FA: 3.03, in FA: 1.92) and TNFα (p = .0044, FDR-adjusted p = .020, median in no FA: 9.16, in FA: 8.64) and may secrete less IFNγ (p = .035, FDR-adjusted p = .11, median in no FA: 6.29, in FA: 5.67) than naive CD4 T cells from non-food allergic controls. No differences between clinical groups were observed for LPS-stimulated monocyte secretion of cytokines. Conclusions These results have important implications for understanding the evolution of the immune response in food allergy throughout childhood, revealing that dendritic cell and T-cell signatures previously identified in early life may persist through to adolescence.

Background: In Western countries, Asian children have higher food allergy risk than Caucasian children. The early-life environmental exposures for this discrepancy are unclear. We aimed to compare prevalence of food allergy and associated risk factors between Asian children in Singapore and Australia. Methods: We studied children in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort (n = 878) and children of Asian ancestry in the HealthNuts cohort (n = 314). Food allergy was defined as a positive SPT ≥3 mm to egg or peanut AND either a convincing history of IgE-mediated reaction at 18 months (GUSTO) or a positive oral food challenge at 14-18 months (HealthNuts). Eczema was defined as parent-reported doctor diagnosis. Results: Food allergy prevalence was 1.1% in Singapore and 15.0% in Australia (P10 months) in Singapore (63.5%) than Australia (16.3%; P

Objective Rates of IgE‐mediated food allergy (FA) have increased over the last few decades, and mounting evidence implicates disruption of epigenetic profiles in various immune cell types in FA development. Recent data implicate B‐cell dysfunction in FA; however, few studies have examined epigenetic changes within these cells. Methods We assessed epigenetic and transcriptomic profiles in purified B cells from adolescents with FA, comparing single‐food‐allergic (peanut only), multi‐food‐allergic (peanut and ≥1 other food) and non‐allergic (control) individuals. Adolescents represent a phenotype of persistent and severe FA indicative of a common immune deviation. Results We identified 144 differentially methylated probes (DMPs) and 116 differentially expressed genes (DEGs) that distinguish B cells of individuals with FA from controls, including differential methylation of the PM20D1 promoter previously associated with allergic disorders. Subgroup comparisons found 729 DMPs specific to either single‐food‐ or multi‐food‐allergic individuals, suggesting epigenetic distinctions between allergy groups. This included two regions with increased methylation near three S100 genes in multi‐food‐allergic individuals. Ontology results of DEGs specific to multi‐food‐allergic individuals revealed enrichment of terms associated with myeloid cell activation. Motif enrichment analysis of promoters associated with DMPs and DEGs showed differential enrichment for motifs recognised by transcription factors regulating B‐ and T‐cell development, B‐cell lineage determination and TGF‐β signalling pathway between the multi‐food‐allergic and single‐food‐allergic groups. Conclusion Our data highlight epigenetic changes in B cells associated with peanut allergy, distinguishing features of the epigenome between single‐food‐ and multi‐food‐allergic individuals and revealing differential developmental pathways potentially underpinning these distinct phenotypes., This study assessed epigenomes and transcriptomes from a cohort of single‐food‐allergic, multi‐food‐allergic and non‐allergic controls. We found distinct B‐cell epigenetic signatures in food‐allergic adolescents and further uncovered multi‐food allergy‐specific methylation signatures, depicting differential regulation of key immune pathways in these clinical groups.

Several recent studies have reported a key role for innate cell hyper-responsiveness in food allergy. This has predominantly been observed in early life, with evidence that innate immune function may return to baseline if food allergy resolves in later childhood. Hallmarks of hyper-responsiveness include increased circulating frequency of monocytes and altered innate cell cytokine responses to in vitro exposure with bacterial endotoxin. These features mirror the defining signatures of trained innate immunity, seen in other complex diseases. In this study, detailed immune cell and cytokine profiling was performed on peripheral blood mononuclear cells at baseline from 27 1 year old infants in the HealthNuts cohort (n = 16 egg allergic and n = 11 non-allergic healthy controls) and following monocyte stimulation. We show that egg allergic infants have increased frequency of circulating monocytes, reduced numbers of regulatory CD4 T cells and increased monocyte: CD4 T cell ratios relative to healthy controls. Monocytes from both egg allergic and non-allergic infants responded to endotoxin stimulation with rapid cytokine production and downregulation of the surface receptor CD16, however monocytes from egg allergic infants were hyper-responsive, producing significantly more inflammatory cytokines (TNFα, IL-6, IL-1β, IL-8) and innate cell recruiting factors (MIP-1α) than healthy controls. This work indicates that monocytes of food allergic infants are programmed to a hyper-inflammatory phenotype and that the development of food allergy may be associated with trained immunity in early life.

Background: Previous research suggests that children who experience asthma may be less physically active, however results have been inconclusive. This study aimed to investigate whether the presence of asthma or wheeze is associated with lower physical activity levels in children, and whether sex, body mass index or earlier asthma or wheeze status modifies the association. Methods: This study was conducted in 391 HealthNuts participants in Melbourne, Australia. Asthma and wheeze data were collected via questionnaire at age 4 and 6 and physical activity was measured through accelerometry. Using adjusted linear regression models, the cross‐sectional and longitudinal associations were investigated. Results: There was no evidence of a difference in time spent in moderate‐to‐vigorous physical activity (MVPA) at age 6 years between children with and without asthma at age 4; children with asthma spent 8.3 minutes more time physically active per day (95%CI: ‐5.6, 22.1, p=0.24) than children without asthma. Similar results were seen for children with current wheeze (5.8 minutes per day more, 95%CI: ‐5.9, 17.5, p=0.33) or ever wheeze or asthma (7.7 min per day more, 95%CI: ‐4.8, 20.2, p=0.23) at age 4 years. Comparable null results were observed in the cross‐sectional analyses. Interaction with BMI could not be assessed, however, previous asthma or wheeze status and sex were not found to modify these associations. Conclusion: This analysis found no evidence of asthma hindering physical activity in these young children. These results are encouraging, as they indicate that the Australian asthma and physical activity public health campaigns are being effectively communicated and adopted by the public. Refereed/Peer-reviewed

Background Environmental microbial exposure plays a role in immune system development and susceptibility to food allergy. Objective We sought to investigate whether infant pacifier use during the first postnatal year, with further consideration of sanitization, alters the risk of food allergy by age 1 year. Methods The birth cohort recruited pregnant mothers at under 28 weeks’ gestation in southeast Australia, with 894 families followed up when infants turned 1 year. Infants were excluded if born under 32 weeks, with a serious illness, major congenital malformation, or genetic disease. Questionnaire data, collected at recruitment and infant ages 1, 6, and 12 months, included pacifier use and pacifier sanitization (defined as the joint exposure of a pacifier and cleaning methods). Challenge-proven food allergy was assessed at 12 months. Results Any pacifier use at 6 months was associated with food allergy (adjusted odds ratio, 1.94; 95% CI, 1.04-3.61), but not pacifier use at other ages. This overall association was driven by the joint exposure of pacifier-antiseptic use (adjusted odds ratio, 4.83; 95% CI, 1.10-21.18) compared with no pacifier use. Using pacifiers without antiseptic at 6 months was not associated with food allergy. Among pacifier users, antiseptic cleaning was still associated with food allergy (adjusted odds ratio, 3.56; 95% CI, 1.18-10.77) compared with no antiseptic use. Furthermore, persistent and repeated antiseptic use over the first 6 months was associated with higher food allergy risk (P = .029). Conclusions This is the first report of a pacifier-antiseptic combination being associated with a higher risk of subsequent food allergy. Future work should investigate underlying biological pathways.

Background Asian children born in Australia have higher rates of eczema and nut allergy than non-Asian children. However, it is not known whether this country of birth differential exists for other allergies or anaphylaxis risk. Objective We investigated the influence of maternal and child's country of birth on the prevalence of parent-reported eczema, asthma, food allergy and being diagnosed by a doctor as being "at risk of anaphylaxis." Methods We assessed the relationship between mother and child country of birth and allergies using the 2010 School Entrant Health Questionnaire, completed for 57 005 5-year old children (85.8% response rate) in Victoria, Australia. Analyses were conducted using logistic regression with results presented as odds ratios (OR) with 95% confidence intervals (CIs). Results Children born in Australia to Asian-born mothers were more likely to have parent-reported food allergy (OR 2.33, 95%CI 1.96-2.77) and eczema (OR 2.04, 95%CI 1.73-2.41), but not more likely to have asthma (OR 0.87, 95% CI 0.74-1.02) than non-Asian children. By contrast, children born in Asia who subsequently migrated to Australia had a lower risk of food allergy (OR 0.33, 95%CI 0.20-0.55), eczema (OR 0.37, 95%CI 0.24-0.57) and asthma (OR 0.29, 95% CI 0.21-0.40). Patterns of anaphylaxis risk differed depending on the trigger. Compared with Australian-born non-Asian children, Australian-born Asian children were more likely to be diagnosed as being at risk of both food-induced and non-food-induced anaphylaxis. For children born in Asia, risk was lower for anaphylaxis to milk, peanut and tree nuts compared to non-Asian children, but higher for soy, wheat and non-food triggers. Conclusions and clinical relevance Patterns of allergy/anaphylaxis risk and their triggers differed according to both ethnicity and country of birth, suggesting a gene-environment factor is in play. The difference in patterns for asthma compared with other atopic diseases is surprising and warrants further exploration.

INTRODUCTION: Eczema is a common childhood ailment responsible for a considerable disease burden. Both timing of introduction to solid food and allergenic food are believed to be related to childhood eczema. Despite the growing body of evidence, the relationship between timing of any solid food introduction (allergenic and/or non-allergenic) and development of eczema has not previously been systematically reviewed. METHODS: PubMed and EMBASE databases were searched using food and eczema terms. Two authors selected papers according to the inclusion criteria and extracted information on study characteristics and measures of association. Meta-analyses were performed after grouping studies according to the age and type of exposure. RESULTS: A total of 17 papers met the inclusion criteria, reporting results from 16 study populations. Of these, 11 were cohort studies, two case controls, one cross sectional study and, 2 randomised controlled trials. Limited meta-analyses were performed due to heterogeneity between studies. Timing of solid food introduction was not associated with eczema. One randomized controlled trial provided weak evidence of an association between early allergenic (around 4 months) food introduction and reduced risk of eczema. CONCLUSIONS: The available evidence is currently insufficient to determine whether the timing of introduction of any solid food influences the risk of eczema. This article is protected by copyright. All rights reserved.

This review summarizes the current state of play with regard to food allergy prevention. Food allergy prevention strategies focused on promoting timely introduction of allergenic foods (predominantly peanut) into the infant diet have recently been introduced in several countries. Additional prevention strategies currently under investigation include optimizing infant vitamin D levels, modulating the gut microbiota through use of probiotics, and preventing eczema to reduce the risk of food sensitization through a damaged skin barrier.

CAPSULE SUMMARY: This study provides the first evidence that early dietary exposure to cashew by age 1 year is associated with reduced risk of cashew allergy in a population-based cohort.

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.

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(long rightwards arrow)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.

Background: Cashew is a common cause of tree nut allergy in children. To date there have been few studies of diagnostic tests for cashew allergy, and positive predictive values (PPVs) for cashew as well as other tree nuts are largely extrapolated from studies of peanut allergy. How relevant these cutoffs are for cashew has not been formally explored. Objective: We aimed to establish skin prick test (SPT) wheal sizes that correlated to 95% PPV for a positive food challenge for cashew. Methods: We included all cashew oral food challenges (OFCs) conducted as part of the HealthNuts (n = 108; age, 4-6 years) and SchoolNuts (n = 37; age, 10-14 years) studies, both recruited from the community (population cohort). A second cohort of all cashew OFCs conducted at the Royal Children's Hospital (RCH) allergy center (n = 343) (2011-2016) and a private allergy clinic based at RCH (n = 43) was included via electronic medical record review (clinic cohort). The 95% PPV for cashew SPT was calculated for both cohorts. Results: Among the population cohort (n = 145), 62% of cashew OFCs were positive compared with 20% of the clinic cohort (n = 386). The SPT cutoff for 95% PPV derived from the population cohort was 10 mm (95% confidence interval [CI], 7.5-12.0). For the clinic cohort, the 95% PPV was 14 mm (95% CI, 9.5-unknown). An SPT wheal size of 8 mm had a PPV of 89% (95% CI, 79-95) in the population cohort and 62% (95% CI, 45-78) in the clinic cohort. Conclusion: A higher SPT wheal size may be more appropriate than the commonly used 8 mm cutoff to guide clinical decisions around when to perform OFC for cashew.

Background Longer duration of breastfeeding may be protective against asthma. However, early manifestations of allergic disease, such as eczema, are risk factors for asthma and can influence the duration of breastfeeding, and hence, may bias observable associations. Objective To examine the relationship between breastfeeding ever and duration and the development of asthma and allergic asthma phenotypes, stratified by a diagnosis of eczema during or after the breastfeeding period. Methods A total of 3663 children participated in the 6-year-old follow-up of the HealthNuts study, a population-based, longitudinal study of allergic diseases in Australia. At age 1 year, breastfeeding and eczema data were collected and at age 6 years, information on wheeze, medication use, and parental report of doctor-diagnosed asthma were obtained, both via questionnaire. Skin prick test responses to food and aeroallergens at age 6 years further distinguished asthmatic children into allergic and nonallergic phenotypes. Results Breastfeeding initiation was not associated with current asthma at age 6 years (adjusted odds ratio, 0.76; 95% CI, 0.45-1.29) when compared with never breastfeeding. Results were similar for length of exclusiveness and overall duration of breastfeeding, and allergic and nonallergic asthma phenotypes. However, increased duration of breastfeeding among children without eczema in infancy was associated with reduced odds of asthma (per month increase, adjusted odds ratio, 0.98; 95% CI, 0.95-1.0; P = .05), which equates to 0.86 (95% CI, 0.74-1.0) reduced odds of asthma for a 6-month increase in breastfeeding. This association was not apparent in children who were diagnosed with eczema during breastfeeding (adjusted odds ratio, 1.03; 95% CI, 0.98-1.08; P = .3). Conclusions Longer duration of breastfeeding was associated with a reduced odds of asthma among children without eczema in the first year of life; this association was masked before stratification by eczema in infancy. Future studies examining breastfeeding practices and the risk of allergic outcomes in later childhood need to consider the presence of early-life allergic manifestations impacting on breastfeeding behavior.

Background: High folate status in pregnancy has been implicated in the increased prevalence of allergic disease, but there are no published data relating directly measured folate status in pregnancy to challenge‐proven food allergy among offspring. The study aim was to examine the association between red blood cell (RBC) folate status in trimester three of pregnancy and allergic disease among offspring. Methods: Red blood cell folate levels were measured at 28‐32 weeks’ gestation in a prospective birth cohort (n = 1074). Food allergy outcomes were assessed in 1‐year‐old infants by skin prick testing and subsequent food challenge. Eczema was assessed by questionnaire and clinical review. High trimester three RBC folate was defined as greater than (>) 1360 nmol/L. Binomial regression was used to examine associations between trimester three RBC folate and allergic outcomes, adjusting for potential confounders. Results: Red blood cell folate levels were measured in 88% (894/1064) of pregnant women. The mean concentration was 1695.6 nmol/L (standard deviation 415.4) with 82% (731/894) >1360 nmol/L. There was no evidence of either linear or non‐linear relationships between trimester three RBC folate and allergic outcomes, nor evidence of associations between high RBC folate and food allergy (adjusted risk ratio (aRR) 2.89, 95% CI 0.90‐9.35), food sensitization (aRR 1.72, 95% CI 0.85‐3.49), or eczema (aRR 0.97, 95% CI 0.67‐1.38). Conclusion: The majority of pregnant women in this study had high RBC folate levels. There was no evidence of associations between trimester three RBC folate and food allergy, food sensitization, or eczema among the offspring, although larger studies are required.

Given an apparent increase in food allergies worldwide, the focus on prevention strategies has intensified. Following the Learning Early About Peanut study, there is now a widespread acceptance that peanut should be introduced promptly into the diet of high-risk infants. However, most food allergies are caused by triggers other than peanut and additional prevention strategies are being evaluated. The appreciation of the role of an impaired skin barrier in the process of food sensitization and subsequent allergy has led to a spectrum of dermatologically orientated studies. Other prevention strategies address the role of the microbiome, dietary components, and other modifiable risk factors. With regard to early introduction of foods other than peanut, studies are heterogeneous in design and governmental and professional society response to the early introduction trials has varied, ranging from new guidelines confining advice specifically to peanut, to ones recommending prompt introduction of a broad spectrum of allergenic foods. Much remains to be determined with regard to the acceptability and uptake of the new guidelines and their impact on infant feeding behavior and food allergy outcomes. This review discusses the panoply of prevention approaches, their promise, and limitations.

Background Randomized controlled trials demonstrate that timely introduction of peanut to infants reduces the risk of peanut allergy. However, much debate remains regarding how to best achieve earlier peanut introduction at the population level. Our previous study in 2007-2011 (HealthNuts, n = 5300) indicated that few infants were consuming peanut in the first year. Australian infant feeding guidelines were updated in 2016 to recommend introducing peanut before 12 months for all infants. There were no data available on the subsequent effect on peanut introduction or peanut reactions. Objective We sought to assess the consequences of a nonscreening approach to allergenic food introduction in a population-based sample of infants in their first year of life. Methods EarlyNuts is a population-based, cross-sectional study of 12-month-old infants in Melbourne, Australia, recruited by using an identical sampling frame and methods to HealthNuts (72% response rate vs 73% response rate in HealthNuts). We report here on the first 860 participants recruited between November 2016 and October 2018. Results Most infants (88.6%; 95% CI, 86.1% to 90.7%) had introduced peanut by 12 months (median age, 6 months), an increase from 28.4% (95% CI, 27.2% to 29.7%) in the HealthNuts study. By 12 months, the majority of these (76.4%) had consumed peanut more than 4 times, and 28% were eating peanut more than once per week. Preliminary results on parent-reported reactions show that 4.0% of those consuming peanut by 12 months had possible IgE-mediated reactions. Conclusions There has been a striking shift toward earlier peanut introduction, with a 3-fold increase in peanut introduction by age 1 year in 2018 compared with 2007-2011.

Background Food allergy is most accurately diagnosed by a formal oral food challenge (OFC); however, it is time and labor intensive, risks the individual to severe reaction, and access is often a limiting step in the diagnostic process. This is compounded for tree nut allergy diagnosis as several OFCs may be required to determine allergy status to each individual tree nut. Accurate diagnosis using minimally invasive diagnostic tests in predicting clinical tree nut allergy is important to correctly identify those with potentially life-threatening reactions and to efficiently and safely tailor nut avoidance to only those nuts deemed allergic to enable less restricted diets and increased food choices for food allergic individuals. Objective To conduct a systematic review on the diagnostic capacity of clinical tests (skin prick test, specific IgE, component-resolved diagnostics, and basophil activation test) to determine OFC-proven or clinical tree nut allergy. Methods We searched 4 electronic databases (OVID Medline, Embase, Cochrane library, and PubMed) until May 2020. Eligible studies were categorized by type of tree nut and diagnostic test. Results A total of 27 studies assessed diagnostic accuracy to a specific tree nut. Overall, the accuracy of diagnostic testing was only reasonable, with 95% positive predictive values established in a small number of tree nuts. Cashew has best diagnostic accuracy, with the cashew component Ana o 3 being most predictive. At the other end of the spectrum, diagnostic testing of almond is poor and of limited clinical use. Conclusion The systematic review highlights the limitations of our current diagnostic tools for tree nut allergy and highlights further areas for research. The unidirectionality of cross-reactivity between cashew/pistachio and walnut/pecan is described and can aid diagnosis. Using diagnostic algorithms such as those demonstrated for walnut/pecan and cashew/pistachio allergy, greater diagnostic accuracy and reduced number of OFCs may be achieved.