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Recent advances in the management of nut allergy

  • Elise Midun
    Correspondence
    Corresponding author.
    Affiliations
    Pediatric Allergy Unit, University Hospitals of Geneva and University of Geneva, Rue Willy Donzé 6, 1205 Geneva, Switzerland, University Lyon 1 Claude Bernard, 43 Boulevard Du 11-Novembre-1918, 69100, Villeurbanne, France
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  • Suzana Radulovic
    Affiliations
    Paediatric Allergy Group, Department of Women and Children's Health, King's College London, London, United Kingdom, Paediatric Allergy Group, Peter Gorer Dept of Immunobiology, School of Immunology & Microbial Sciences, King's College London, Guys' Hospital, London, United Kingdom, Children's Allergy Service, Evelina Children's Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, United Kingdom
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  • Helen Brough
    Affiliations
    Paediatric Allergy Group, Department of Women and Children's Health, King's College London, London, United Kingdom, Paediatric Allergy Group, Peter Gorer Dept of Immunobiology, School of Immunology & Microbial Sciences, King's College London, Guys' Hospital, London, United Kingdom, Children's Allergy Service, Evelina Children's Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, United Kingdom
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  • Jean-Christoph Caubet
    Affiliations
    Pediatric Allergy Unit, University Hospitals of Geneva and University of Geneva, Rue Willy Donzé 6, 1205, Geneva, Switzerland
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Open AccessPublished:January 12, 2021DOI:https://doi.org/10.1016/j.waojou.2020.100491

      Abstract

      Peanut/tree nut allergy is common and has been associated with particularly severe reactions. Epidemiological data have shown that the prevalence ranges between 0.05% and 4.9% for tree nut and between 0.5% and 3% for peanut. These large variations can be explained by differences in the age of included patients and the geographical region. In addition, the food consumption modality (ie, raw versus roasted) plays a major role, as heat treatment has the capacity to modify the allergenicity of nuts and legumes. Nut allergies tend to persist into adulthood and consequently have a high impact on quality of life.
      Recently, it has been demonstrated that a significant proportion of nut allergic patients are able to tolerate other nuts. As opposed to the avoidance of all nuts, this approach is currently proposed in several tertiary allergy centers. However, diagnosis of nut allergy is particularly difficult due to co-sensitization leading to high rate of false positive skin prick tests and/or specific IgE to whole allergen extracts. The use of component resolved diagnosis leads to major improvement of diagnosis, particularly to distinguish between primary and secondary nut allergies. The basophil activation test has been suggested to be useful but is still used mainly as a research tool. Thus, diagnosis remains mainly based on the oral food challenge, which is considered as the gold standard.
      Regarding treatment, avoidance remains the cornerstone of management of nut allergy. Oral immunotherapy is increasingly proposed as an alternative management strategy.

      Keywords

      Abbreviations:

      Tree nut (TN), Oral allergy syndrome (OAS), Component-resolved diagnostic (CRD), Skin prick test (SPT), Pathogenesis related protein type 10 (PR-10), Lipid transfer protein (LTP), Oral food challenge (OFC), Double-blind, placebo-controlled, food challenge (DBPCFC), Oral induction tolerance (OIT), Platelet-activating factor (PAF), Pollen-food syndrome (PFS), Precautionary Allergen Labels ((PAL))

      Introduction

      Peanut and Tree nut (TN) allergies are one of the most common food allergies worldwide and constitute a major public health problem. The estimated prevalence of peanut/tree nut allergies is approximatively 2%.
      • McWilliam V.
      • Koplin J.
      • Lodge C.
      • Tang M.
      • Dharmage S.
      • Allen K.
      The Prevalence of Tree Nut Allergy: A Systematic Review.
      • Sicherer S.H.
      • Muñoz-Furlong A.
      • Godbold J.H.
      • Sampson H.A.
      US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up.
      • Du Toit G.
      • Katz Y.
      • Sasieni P.
      • et al.
      Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy.
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Matsui E.C.
      • Wood R.A.
      The natural history of tree nut allergy.
      There is a large variation in prevalence reported in different countries, ie, from 0.05% to 4.9% for tree nut and between 0.5% and 3% for peanut.
      • McWilliam V.
      • Koplin J.
      • Lodge C.
      • Tang M.
      • Dharmage S.
      • Allen K.
      The Prevalence of Tree Nut Allergy: A Systematic Review.
      ,
      • Du Toit G.
      • Katz Y.
      • Sasieni P.
      • et al.
      Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy.
      ,
      • Rona R.J.
      • Keil T.
      • Summers C.
      • et al.
      The prevalence of food allergy: a meta-analysis.
      • Hourihane J.O.
      • Dean T.P.
      • Warner J.O.
      Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges.
      • Osborne N.J.
      • Koplin J.J.
      • Martin P.E.
      • et al.
      Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants.
      Peanut allergy is the most common nut allergy. The allergy prevalence for each tree nut seems to vary in different parts of the world.
      • McWilliam V.
      • Koplin J.
      • Lodge C.
      • Tang M.
      • Dharmage S.
      • Allen K.
      The Prevalence of Tree Nut Allergy: A Systematic Review.
      ,
      • Osborne N.J.
      • Koplin J.J.
      • Martin P.E.
      • et al.
      Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants.
      • Prescott S.L.
      • Pawankar R.
      • Allen K.J.
      • et al.
      A global survey of changing patterns of food allergy burden in children.
      • Nwaru B.I.
      • Hickstein L.
      • Panesar S.S.
      • et al.
      Prevalence of common food allergies in Europe: a systematic review and meta-analysis.
      • Moneret-Vautrin D.-A.
      Épidémiologie de l’allergie alimentaire.
      Indeed, hazelnut allergy is the most frequent tree nut allergy in continental Europe; Brazil nut, walnut and almond are most commonly reported in the United Kingdom;
      • McWilliam V.
      • Koplin J.
      • Lodge C.
      • Tang M.
      • Dharmage S.
      • Allen K.
      The Prevalence of Tree Nut Allergy: A Systematic Review.
      ,
      • Brough H.A.
      • Caubet J.-C.
      • Mazon A.
      • et al.
      Defining challenge-proven coexistent nut and sesame seed allergy: a prospective multicenter European study.
      and walnut and cashew nut allergy are the most common tree nut allergies in the United States.
      • McWilliam V.
      • Koplin J.
      • Lodge C.
      • Tang M.
      • Dharmage S.
      • Allen K.
      The Prevalence of Tree Nut Allergy: A Systematic Review.
      ,
      • Marchisotto M.J.
      • Harada L.
      • Kamdar O.
      • et al.
      Food allergen labeling and purchasing habits in the United States and Canada.
      These differences are mainly due to the variation of nuts consumed in different countries. However, prevalence variations have also been reported within the same country, highlighting the possible influence of environmental factors such as pollen exposure.
      • McWilliam V.
      • Koplin J.
      • Lodge C.
      • Tang M.
      • Dharmage S.
      • Allen K.
      The Prevalence of Tree Nut Allergy: A Systematic Review.
      ,
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Matsui E.C.
      • Wood R.A.
      The natural history of tree nut allergy.
      An important aspect of nut allergy is the risk of potentially life-threatening allergic reactions. Indeed, nut allergies have been associated with severe allergic reactions more commonly than the majority of other foods. Recent studies reported that peanut/TN allergies account for 70–90% of fatalities from food-induced anaphylaxis, with TN alone accounting for 18–40%.
      • Smeekens J.M.
      • Bagley K.
      • Kulis M.
      Tree nut allergies: allergen homology, cross-reactivity, and implications for therapy.
      Peanut and TN allergies also tend to persist, and the acquisition of natural tolerance to peanut/TN occurs in only 9%–20% of peanut/TN allergic patients.
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Matsui E.C.
      • Wood R.A.
      The natural history of tree nut allergy.
      Despite years of research and clinical efforts, strict avoidance of the incriminated nut (peanut/TN) remains the cornerstone of management. Thus, quality of life (QoL) is reduced with increasing stress and anxiety due to the need for constant vigilance.
      • King R.M.
      • Knibb R.C.
      • Hourihane J.O.
      Impact of peanut allergy on quality of life, stress and anxiety in the family.
      ,
      • McWilliam V.
      • Peters R.
      • Tang M.L.K.
      • et al.
      Patterns of tree nut sensitization and allergy in the first 6 years of life in a population-based cohort.
      Although other treatment options, such as oral immunotherapy, have been largely investigated for peanut and TN allergic patients, their use currently remains limited.
      • Muraro A.
      • Werfel T.
      • Hoffmann-Sommergruber K.
      • et al.
      EAACI Food Allergy and Anaphylaxis Guidelines: diagnosis and management of food allergy.
      Management of patients with peanut/TN allergy is often quite complex. The distinction between cross-sensitization and clinically relevant cross-reactivity between TN and also peanut can be difficult and often requires multiple investigations and oral food challenges (OFC). While avoidance of all nuts has been the rule for a long time in patients allergic to one nut, the possible introduction of other nuts has recently been investigated in several studies.
      • Eigenmann P.A.
      • Lack G.
      • Mazon A.
      • et al.
      Managing nut allergy: a remaining clinical challenge.
      • Weinberger T.
      • Sicherer S.
      Current perspectives on tree nut allergy: a review.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      Walnut oral immunotherapy for desensitisation of walnut and additional tree nut allergies (Nut CRACKER): a single-centre, prospective cohort study.
      • Wasserman R.L.
      • Hague A.R.
      • Pence D.M.
      • et al.
      Real-world experience with peanut oral immunotherapy: lessons learned from 270 patients.
      For the purpose of this review, we will discuss these different aspects constituting advances in the management of nut allergies.

      Proportion of patients reacting to multiple nuts

      Prevalence of co-sensitization and co-allergy

      Co-existent allergy peanut and TN have been described for many years. Initially, in the 90s, Sicherer et al reported that 34% of patients allergic to peanut or 1 TN may present with multiple nut allergy.
      • Sicherer S.H.
      • Burks A.W.
      • Sampson H.A.
      Clinical features of acute allergic reactions to peanut and tree nuts in children.
      However, further studies reported a large variation in the proportion of patients reacting to multiple nuts, ranging from 12% to 96.7%.
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Matsui E.C.
      • Wood R.A.
      The natural history of tree nut allergy.
      ,
      • McWilliam V.
      • Peters R.
      • Tang M.L.K.
      • et al.
      Patterns of tree nut sensitization and allergy in the first 6 years of life in a population-based cohort.
      ,
      • Sicherer S.H.
      • Burks A.W.
      • Sampson H.A.
      Clinical features of acute allergic reactions to peanut and tree nuts in children.
      • Sicherer S.H.
      • Furlong T.J.
      • Muñoz-Furlong A.
      • Burks A.W.
      • Sampson H.A.
      A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants.
      • McWilliam V.L.
      • Koplin J.J.
      • Field M.J.
      • et al.
      Self-reported adverse food reactions and anaphylaxis in the SchoolNuts study: a population-based study of adolescents.
      • Maloney J.M.
      • Rudengren M.
      • Ahlstedt S.
      • Bock S.A.
      • Sampson H.A.
      The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.
      • Anagnostou A.
      Insights into tree nut and sesame consumption from a cohort of 80 peanut-allergic children.
      • Cousin M.
      • Verdun S.
      • Seynave M.
      • et al.
      Phenotypical characterization of peanut allergic children with differences in cross-allergy to tree nuts and other legumes.
      • Ball H.
      • Luyt D.
      • Bravin K.
      • Kirk K.
      Single nut or total nut avoidance in nut allergic children: outcome of nut challenges to guide exclusion diets.
      • Yang L.
      • Clements S.
      • Joks R.
      A retrospective study of peanut and tree nut allergy: sensitization and correlations with clinical manifestations.
      These data have been summarized in Table 1.
      Table 1
      Proportion of co-sensitizationProportion of self-reported co-allergyProportion of co-allergy confirmed by OFC
      Sicherer et al.
      • Sicherer S.H.
      • Burks A.W.
      • Sampson H.A.
      Clinical features of acute allergic reactions to peanut and tree nuts in children.
      34%
      Maloney et al.
      • Maloney J.M.
      • Rudengren M.
      • Ahlstedt S.
      • Bock S.A.
      • Sampson H.A.
      The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.
      86%34%
      Anagnostou et al.
      • Anagnostou A.
      Insights into tree nut and sesame consumption from a cohort of 80 peanut-allergic children.
      80%
      Cousin et al.
      • Cousin M.
      • Verdun S.
      • Seynave M.
      • et al.
      Phenotypical characterization of peanut allergic children with differences in cross-allergy to tree nuts and other legumes.
      87,1%43,2%
      Ball et al.
      • Ball H.
      • Luyt D.
      • Bravin K.
      • Kirk K.
      Single nut or total nut avoidance in nut allergic children: outcome of nut challenges to guide exclusion diets.
      23,4% of peanut-allergic patients are sensitized to nuts. 25,4% of patients allergic to nuts are sensitized to peanuts or other nuts.32% of peanut-allergic patients are sensitized to nuts.

      38% patients allergic to nuts are allergic to peanuts or other nuts.
      Yang et al.
      • Yang L.
      • Clements S.
      • Joks R.
      A retrospective study of peanut and tree nut allergy: sensitization and correlations with clinical manifestations.
      51% of patients allergic to nuts are sensitized to peanut73% of patients allergic to peanut are sensitized to nuts
      Clark et al.
      • Clark A.T.
      • Ewan P.W.
      The development and progression of allergy to multiple nuts at different ages.
      At 2 yr of age: 19% of children were multi-sensitizedAt 5-14 yr: 86% were multi sensitized2% of children were multi allergic

      At 14yr: 47% of children were multi-allergic
      Elizur et al.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      60,6 %to 96,7%<30%
      Couch et al.
      • Couch C.
      • Franxman T.
      • Greenhawt M.
      Characteristics of tree nut challenges in tree nut allergic and tree nut sensitized individuals.
      12%
      Brough et al.
      • Brough H.A.
      • Caubet J.-C.
      • Mazon A.
      • et al.
      Defining challenge-proven coexistent nut and sesame seed allergy: a prospective multicenter European study.
      60,7%
      OFC: oral food challenge, yr: year.
      The influence of pollen allergy, the population studied as well as its ethnicity are all confounding factors that might influence the results. In addition, these differences can be explained by differences in the methodology of the studies.
      Thus, studies that reported on specific IgE found that the co-sensitization rate among TN and peanut ranged between 60.6% and 96.7%.
      • Maloney J.M.
      • Rudengren M.
      • Ahlstedt S.
      • Bock S.A.
      • Sampson H.A.
      The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.
      • Anagnostou A.
      Insights into tree nut and sesame consumption from a cohort of 80 peanut-allergic children.
      • Cousin M.
      • Verdun S.
      • Seynave M.
      • et al.
      Phenotypical characterization of peanut allergic children with differences in cross-allergy to tree nuts and other legumes.
      ,
      • Yang L.
      • Clements S.
      • Joks R.
      A retrospective study of peanut and tree nut allergy: sensitization and correlations with clinical manifestations.
      • Clark A.T.
      • Ewan P.W.
      The development and progression of allergy to multiple nuts at different ages.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      When a positive clinical history is required to diagnose nut allergy, but without a confirmatory OFC, the proportion of patients with multiple nut allergy is lower than expected, ranging between 23% and 68%
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Matsui E.C.
      • Wood R.A.
      The natural history of tree nut allergy.
      ,
      • Sicherer S.H.
      • Burks A.W.
      • Sampson H.A.
      Clinical features of acute allergic reactions to peanut and tree nuts in children.
      • Sicherer S.H.
      • Furlong T.J.
      • Muñoz-Furlong A.
      • Burks A.W.
      • Sampson H.A.
      A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants.
      • McWilliam V.L.
      • Koplin J.J.
      • Field M.J.
      • et al.
      Self-reported adverse food reactions and anaphylaxis in the SchoolNuts study: a population-based study of adolescents.
      • Maloney J.M.
      • Rudengren M.
      • Ahlstedt S.
      • Bock S.A.
      • Sampson H.A.
      The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.
      • Anagnostou A.
      Insights into tree nut and sesame consumption from a cohort of 80 peanut-allergic children.
      (Table 1).
      Studies including OFCs to prove co-existent peanut/TN allergy, considered as the gold standard, report a rate co-existent allergy of 12%–38.8% and confirmed initial data by Sicherer
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Matsui E.C.
      • Wood R.A.
      The natural history of tree nut allergy.
      ,
      • McWilliam V.
      • Peters R.
      • Tang M.L.K.
      • et al.
      Patterns of tree nut sensitization and allergy in the first 6 years of life in a population-based cohort.
      ,
      • Cousin M.
      • Verdun S.
      • Seynave M.
      • et al.
      Phenotypical characterization of peanut allergic children with differences in cross-allergy to tree nuts and other legumes.
      ,
      • Ball H.
      • Luyt D.
      • Bravin K.
      • Kirk K.
      Single nut or total nut avoidance in nut allergic children: outcome of nut challenges to guide exclusion diets.
      (Table 1). However, a recent prospective multicenter study in Europe (Pronuts study) based on 122 patients that underwent sequential OFC to determine allergy versus tolerance, showed a higher rate of co-existent peanut/TN or sesame seed allergy at 60.7%.
      • Brough H.A.
      • Caubet J.-C.
      • Mazon A.
      • et al.
      Defining challenge-proven coexistent nut and sesame seed allergy: a prospective multicenter European study.
      These results could be explained by the fact that the Pronuts study was prospective as opposed to retrospective in the previous studies,
      • Ball H.
      • Luyt D.
      • Bravin K.
      • Kirk K.
      Single nut or total nut avoidance in nut allergic children: outcome of nut challenges to guide exclusion diets.
      ,
      • Couch C.
      • Franxman T.
      • Greenhawt M.
      Characteristics of tree nut challenges in tree nut allergic and tree nut sensitized individuals.
      assessed all 9 TNs (compared to other studies testing less TNs),
      • Ball H.
      • Luyt D.
      • Bravin K.
      • Kirk K.
      Single nut or total nut avoidance in nut allergic children: outcome of nut challenges to guide exclusion diets.
      ,
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      and included sesame seed which belongs to the Pedaliaceae (seeds) family. The NutCracker study which was also a prospective study including OFCs, reported a lower prevalence of multiple nut allergy below 30%,
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      however, this study (based on a cohort of 83 children with TN allergy in Israel) included only OFCs to a subset of TN (walnut, pecan, cashew, pistachio, hazelnut, and almond), which could potentially underestimate the rate of co-existent allergy.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      Couch et al in a recent retrospective study, found similar results; 67 patients with a history of TN allergy underwent an OFC to another TN to which they were sensitized, but not exposed to before. Interestingly, only 14% of the included patients had a positive OFC to another TN. However, this study was retrospective and patients in this study had relatively low levels of specific IgE (90% of these patients had a sIgE <2 kU/L and at least half had a level <0.35 kU/L); thus, these patients were probably selected for OFC based on lower IgE tests to confirm non-allergy by OFC and this would have contributed to an underestimation of co-existent peanut/TN allergy.
      • Couch C.
      • Franxman T.
      • Greenhawt M.
      Characteristics of tree nut challenges in tree nut allergic and tree nut sensitized individuals.

      Development of peanut/TN allergy

      The age of participants may also play a role in the rate of co-existent peanut/TN allergy. Indeed, although most TN allergies become apparent when a patient is young, many studies have shown that the rate of co-existent allergy between peanut and TN increases with age. The HealthNuts study showed that children who had peanut allergy at 1 year old had a 27% chance of having an OFC-confirmed TN allergy at 6 years of age.
      • McWilliam V.
      • Peters R.
      • Tang M.L.K.
      • et al.
      Patterns of tree nut sensitization and allergy in the first 6 years of life in a population-based cohort.
      Brough et al in a retrospective study reported similar results.
      • Brough H.A.
      • Costa J.
      • Penagos M.
      • et al.
      Increase in multiple nut reactivity with increasing age is not an artefact of incomplete allergy testing.
      This increase can be explained particularly by the fact that nuts are introduced later than other foods. Indeed, Clark and Ewan showed that the number of nut consumption increased with age (23% eating more than one nut at 2 years, versus 73% by 10 years); they postulated that this could lead to higher rates of multisensitization (19% at 2 years, 86% at 5–14 years) and multiallergy (2% at 2 years to 47% at 14 years).
      • Clark A.T.
      • Ewan P.W.
      The development and progression of allergy to multiple nuts at different ages.
      Conversely, Elizur et al proposed the opposite hypothesis, that elimination of TN in multiple-food-allergic patients could promote the development of sensitization and allergy to TN years later.
      • Elizur A.
      • Bollyky J.B.
      • Block W.M.
      Elimination diet and the development of multiple tree-nut allergies: this work was done as part of Dr. Elizur's sabbatical from Sackler School of Medicine, Tel Aviv University, Israel.
      Peanut/TN co-sensitizations are common and distinguishing asymptomatic sensitization from clinical food allergy is currently based on OFCs, whicht may lead to life-threatening reactions. The clinical relevance of serological cross-reactivity between peanut/TN therefore needs to be better defined.
      Peanut/TN allergy has 2 main dimensions. One is the cross-reactivity for the components, and another is severity. Recent advances in the field of component resolved diagnostics (CRD) provides the clinician with more information as to whether the patient has secondary nut allergy due to pollen food syndrome (also known as oral allergy syndrome) or primary nut allergy, more likely to lead to systemic symptoms.

      Co-allergy and co-sensitization

      Indeed, there are different sensitization profiles in peanut/TN allergy. Patients can be, therefore, sensitized to different families of proteins within the nut. The physico-chemical properties of the proteins to which peanut/TN allergic patients may be sensitized are responsible for allergic reactions of varying severity. The most well-known protein family is the seed storage protein family (eg, Ara h 2, Cor a 9, Cor a 14) responsible for severe anaphylactic reactions, explained in part by their thermostability and digestive resistance. Other families of proteins that are also responsible for severe reactions are the oleosins, defensin and LTP family.
      Other sensitization patterns can lead to less severe symptoms in the majority of cases, such as the reprensented sensitization to PR-10 and profilins family. This is due to the fact that these protein families are degraded by heat and digestion.
      • Matricardi P.M.
      • Kleine-Tebbe J.
      • Hoffmann H.J.
      • et al.
      EAACI molecular allergology user's guide.
      Components, protein families and cross-reactivity between components are referenced in Table 2.
      Table 2
      ComponentProtein FamilyCo Sensitization/Cross Reactivity
      Tree nut
      Hazelnut
      • Weinberger T.
      • Sicherer S.
      Current perspectives on tree nut allergy: a review.
      • Geiselhart S.
      • Hoffmann-Sommergruber K.
      • Bublin M.
      Tree nut allergens.
      Cor a 1PR-10
      Cor a 2Profilin
      Cor a 8LTPAra h 9, Jug r 3
      Cor a 9legumin
      Cor a 11Vicilin
      Cor a 12Oleosin
      Cor a 13Oleosin
      Cor a 142S albumin
      Cashew
      • Weinberger T.
      • Sicherer S.
      Current perspectives on tree nut allergy: a review.
      • Geiselhart S.
      • Hoffmann-Sommergruber K.
      • Bublin M.
      Tree nut allergens.
      Ana o 1VicilinPis v 5
      Ana o 2LeguminPis v 2
      Ana o 32S albuminPis v 1
      Pistachio
      • Weinberger T.
      • Sicherer S.
      Current perspectives on tree nut allergy: a review.
      • Geiselhart S.
      • Hoffmann-Sommergruber K.
      • Bublin M.
      Tree nut allergens.
      • Costa J.
      • Silva I.
      • Vicente A.A.
      • Oliveira M.B.P.P.
      • Mafra I.
      Pistachio nut allergy: an updated overview.
      Pis v 12S albuminAna o 3
      Pis v 2LeguminAna o 2
      Pis v 3Vicilin
      Pis v 4
      Pis v 5LeguminAna o 1
      Walnut
      • Geiselhart S.
      • Hoffmann-Sommergruber K.
      • Bublin M.
      Tree nut allergens.
      • Costa J.
      • Carrapatoso I.
      • Oliveira M.B.P.P.
      • Mafra I.
      Walnut allergens: molecular characterization, detection and clinical relevance.
      Jug r 12S albuminCar i 1
      Jug r 2Vicilin
      Jug r 3LTPCor a 8, Arah 9
      Jug r 4LeguminCar i 4
      Jug r 5PR-10
      Jug r 6Vicilin
      Jug r 7Profilin
      Pecan
      • Weinberger T.
      • Sicherer S.
      Current perspectives on tree nut allergy: a review.
      • Geiselhart S.
      • Hoffmann-Sommergruber K.
      • Bublin M.
      Tree nut allergens.
      Car i 12S albuminJug r 1
      Car i 2Vicilin
      Car i 4LeguminJug r 4
      Almond
      • Costa J.
      • Mafra I.
      • Carrapatoso I.
      • Oliveira M.B.P.P.
      Almond allergens: molecular characterization, detection, and clinical relevance.
      Pru du 1PR-10
      Pru du 2PR-5
      Pru du 3LTP
      Pru du 4ProfilinAra h 9, Cor a 8, Jug r 3
      Pru du 5
      Pru du 6Legumin
      Brazil nut
      • Weinberger T.
      • Sicherer S.
      Current perspectives on tree nut allergy: a review.
      • Geiselhart S.
      • Hoffmann-Sommergruber K.
      • Bublin M.
      Tree nut allergens.
      Ber e 12S albumin
      Ber e 2Legumin
      Legumes
      Peanut
      • Verma A.K.
      • Kumar S.
      • Das M.
      • Dwivedi P.D.
      A comprehensive review of legume allergy.
      • Cabanillas B.
      • Jappe U.
      • Novak N.
      Allergy to peanut, soybean, and other legumes: recent advances in allergen characterization, stability to processing and IgE cross-reactivity.
      • Chan E.S.
      • Greenhawt M.J.
      • Fleischer D.M.
      • Caubet J.-C.
      Managing cross-reactivity in those with peanut allergy.
      Arah 1VicilinGly m 5
      Arah 22S albuminGly m 8
      Arah 3LeguminGly m 6
      Arah 4LeguminGly m 6
      Arah 5ProfilinGly m 3, lup a 5
      Arah 62S albumin
      Arah 72S albumin
      Arah 8PR-10Gly m 4
      Arah 9LTPGlym 1, Cor a 8, Jug r 3
      Arah 10Oleosin
      Arah 11Oleosin
      Arah 12DefensinGly m 2
      Arah 13DefensinGly m 2
      Arah 14Oleosin
      Arah 15Oleosin
      Arah 16LTP
      Arah 17LTP
      Gly m 1LTPAra h 9
      Gly m 2DefensinArah 12, 13
      Gly m 3ProfilinArah 5, Lup a 5
      Gly m 4PR-10Arah 8
      Gly m 5VicilinAra h1
      Gly m 6LeguminA ra h 3-4
      Gly m 7
      Gly m 82S albuminAra h 2
      Lupin
      • Verma A.K.
      • Kumar S.
      • Das M.
      • Dwivedi P.D.
      A comprehensive review of legume allergy.
      • Cabanillas B.
      • Jappe U.
      • Novak N.
      Allergy to peanut, soybean, and other legumes: recent advances in allergen characterization, stability to processing and IgE cross-reactivity.
      • Chan E.S.
      • Greenhawt M.J.
      • Fleischer D.M.
      • Caubet J.-C.
      Managing cross-reactivity in those with peanut allergy.
      Lup a 1Vicilin
      Lup a vicilinVicilin
      Lup a 5Profilin
      Lup an 11SVicilin
      Seed
      Sesame seed
      • Adatia A.
      • Clarke A.
      • Yanishevsky Y.
      • Ben-Shoshan M.
      Sesame allergy: current perspectives.
      Ses i 12 S albuminNo available data
      Ses i 22 S albuminNo available data
      Ses i 3VicilinNo available data
      Ses i 4OleosinNo available data
      Ses i 5OleosinNo available data
      Ses i 6LeguminNo available data
      Ses i 7LeguminNo available data
      PR-10: pathogenesis related protein type 10, LTP: lipid transfer protein.

      Structural homology

      Allergies to certain well-defined combinations of nuts may be due to the presence of similar or closely related epitopes. Such closely related epitopes are more common in phylogenetically closely related nuts such as cashew and pistachio, walnut and pecan,
      • Smeekens J.M.
      • Bagley K.
      • Kulis M.
      Tree nut allergies: allergen homology, cross-reactivity, and implications for therapy.
      ,
      • Maloney J.M.
      • Rudengren M.
      • Ahlstedt S.
      • Bock S.A.
      • Sampson H.A.
      The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.
      ,
      • Andorf S.
      • Borres M.P.
      • Block W.
      • et al.
      Association of clinical reactivity with sensitization to allergen components in multifood-allergic children.
      ,
      • Geiselhart S.
      • Hoffmann-Sommergruber K.
      • Bublin M.
      Tree nut allergens.
      peanut and soybean.
      • Matricardi P.M.
      • Kleine-Tebbe J.
      • Hoffmann H.J.
      • et al.
      EAACI molecular allergology user's guide.
      ,
      • Chruszcz M.
      • Maleki S.J.
      • Majorek K.A.
      • et al.
      Structural and immunologic characterization of Ara h 1, a major peanut allergen.
      • Hurlburt B.K.
      • Offermann L.R.
      • McBride J.K.
      • Majorek K.A.
      • Maleki S.J.
      • Chruszcz M.
      Structure and function of the peanut panallergen Ara h 8.
      • Beardslee T.A.
      • Zeece M.G.
      • Sarath G.
      • Markwell J.P.
      Soybean glycinin G1 acidic chain shares IgE epitopes with peanut allergen Ara h 3.
      • Verma A.K.
      • Kumar S.
      • Das M.
      • Dwivedi P.D.
      A comprehensive review of legume allergy.
      Thus, the Pronuts and NutCracker studies found that 97%–100% of pistachio and pecan allergic children were allergic to cashew nut and walnut, respectively.
      • Brough H.A.
      • Caubet J.-C.
      • Mazon A.
      • et al.
      Defining challenge-proven coexistent nut and sesame seed allergy: a prospective multicenter European study.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      Moreover, 64.2%–83.3% of patient allergic to cashew or walnut were respectively co-allergic to pistachio and pecan.
      • Brough H.A.
      • Caubet J.-C.
      • Mazon A.
      • et al.
      Defining challenge-proven coexistent nut and sesame seed allergy: a prospective multicenter European study.
      ,
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      In a retrospective study, Andorf and al reported similar results.
      • Andorf S.
      • Borres M.P.
      • Block W.
      • et al.
      Association of clinical reactivity with sensitization to allergen components in multifood-allergic children.
      Pistachio and cashew nuts belong to the same Anarcadiaceae family (homology 79% between rPis v 3 and rAna o 1, and homology 66% between Pis v 1 and r Ana o 3).
      • Smeekens J.M.
      • Bagley K.
      • Kulis M.
      Tree nut allergies: allergen homology, cross-reactivity, and implications for therapy.
      ,
      • Willison L.N.
      • Tawde P.
      • Robotham J.M.
      • et al.
      Pistachio vicilin, Pis v 3, is immunoglobulin E-reactive and cross-reacts with the homologous cashew allergen, Ana o 1.
      High homology between pecan and walnut protein sequences, which belong to the same botanical family (the Juglandaceae family), have also been described. Indeed, 2S albumin allergens in walnut (Jug r 1) and pecan (Car i 1) have 88% sequence identity and legumin allergens in walnut (Jug r 4) and pecan (Car i 4) have 95% sequence identity.
      • Smeekens J.M.
      • Bagley K.
      • Kulis M.
      Tree nut allergies: allergen homology, cross-reactivity, and implications for therapy.
      Other studies have reported lower prevalence of co-allergy between cashew nut and pistachio. Indeed, Van der Valk et al and the HealthNut studies found that only 31%–36% of the cashew-allergic patients reacted to pistachio.
      • McWilliam V.
      • Peters R.
      • Tang M.L.K.
      • et al.
      Patterns of tree nut sensitization and allergy in the first 6 years of life in a population-based cohort.
      ,
      • van der Valk J.P.M.
      • Bouche R.E.
      • Gerth van Wijk R.
      • et al.
      Low percentage of clinically relevant pistachio nut and mango co-sensitisation in cashew nut sensitised children.
      There is an uni-directionality of the co-existent allergies, as a lower proportion of patients allergic to walnut and cashew are allergic to pecan and pistachio, respectively. This suggests that some allergenic proteins are shared while others are unique to cashew and walnut and therefore result in mono-allergy.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      For peanut and soybean, studies have demonstrated similarities between both legumes allergens, such as Ara h 1, Ara h 3, and Ara h 8 with Gly m 5, Gly m 6, and Gly m 4, respectively, between 38,4%–70%
      • Matricardi P.M.
      • Kleine-Tebbe J.
      • Hoffmann H.J.
      • et al.
      EAACI molecular allergology user's guide.
      ,
      • Chruszcz M.
      • Maleki S.J.
      • Majorek K.A.
      • et al.
      Structural and immunologic characterization of Ara h 1, a major peanut allergen.
      • Hurlburt B.K.
      • Offermann L.R.
      • McBride J.K.
      • Majorek K.A.
      • Maleki S.J.
      • Chruszcz M.
      Structure and function of the peanut panallergen Ara h 8.
      • Beardslee T.A.
      • Zeece M.G.
      • Sarath G.
      • Markwell J.P.
      Soybean glycinin G1 acidic chain shares IgE epitopes with peanut allergen Ara h 3.
      • Verma A.K.
      • Kumar S.
      • Das M.
      • Dwivedi P.D.
      A comprehensive review of legume allergy.
      (Table 2). Despite this homology, studies show a low rate of cross sensitization and cross reaction. Indeed, in a study from several years ago, 31% of peanut-allergic children had cosensitization with soy, and only 3% had clinical reactivity to soy.
      • Bock S.A.
      • Atkins F.M.
      The natural history of peanut allergy.
      In other studies, the cross-reactivity rate has been estimated to be between 6.5% and 15%.
      • Skolnick H.S.
      • Conover-Walker M.K.
      • Koerner C.B.
      • Sampson H.A.
      • Burks W.
      • Wood R.A.
      The natural history of peanut allergy.
      ,
      • Bernhisel-Broadbent J.
      • Sampson H.A.
      Cross-allergenicity in the legume botanical family in children with food hypersensitivity.
      Another study by Savage et al reported that 98% of patients with a soy allergy also had a peanut allergy.
      • Savage J.H.
      • Kaeding A.J.
      • Matsui E.C.
      • Wood R.A.
      The natural history of soy allergy.
      As with nut allergies, these data suggest that some proteins are common to peanut and soybean and some are specific to soybean and peanut.

      Protein families

      Different families of proteins such as the seed storage protein families (vicillins, 2 S albumins and legumes), the family of lipid transfer proteins (LTP) family, and pathogenesis-related protein type 10 (PR-10) family also help explain the cross-reactivity among peanuts and other legumes (eg, peanut-lupine). In addition, they also help explain, in part, why unrelated nuts such as TN and peanuts may exhibit serological and clinical cross-reactivity.
      • Du Toit G.
      • Katz Y.
      • Sasieni P.
      • et al.
      Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy.
      ,
      • Cousin M.
      • Verdun S.
      • Seynave M.
      • et al.
      Phenotypical characterization of peanut allergic children with differences in cross-allergy to tree nuts and other legumes.
      ,
      • Ball H.
      • Luyt D.
      • Bravin K.
      • Kirk K.
      Single nut or total nut avoidance in nut allergic children: outcome of nut challenges to guide exclusion diets.

      Seed storage protein family

      Peanut and lupine have a high degree of cross-reactivity; therefore, risk associated with cross reaction is also high as compared to other legumes. Studies show that 14.5%–89% of peanut allergic patients were sensitized to lupine however this cross sensitivity is clinically significant in only 4%–35% of cases.
      • Gayraud J.
      • Mairesse M.
      • Fontaine J.F.
      • et al.
      The prevalence of sensitization to lupin flour in France and Belgium: a prospective study in 5,366 patients, by the Allergy Vigilance Network.
      • Moneret-Vautrin D.A.
      • Guérin L.
      • Kanny G.
      • Flabbee J.
      • Frémont S.
      • Morisset M.
      Cross-allergenicity of peanut and lupine: the risk of lupine allergy in patients allergic to peanuts.
      • Shaw J.
      • Roberts G.
      • Grimshaw K.
      • White S.
      • Hourihane J.
      Lupin allergy in peanut-allergic children and teenagers.
      • Reis A.M.
      • Fernandes N.P.
      • Marques S.L.
      • et al.
      Lupine sensitisation in a population of 1,160 subjects.
      • Peeters K.A.B.M.
      • Koppelman S.J.
      • Penninks A.H.
      • et al.
      Clinical relevance of sensitization to lupine in peanut-sensitized adults.
      • Fiocchi A.
      • Sarratud P.
      • Terracciano L.
      • et al.
      Assessment of the tolerance to lupine-enriched pasta in peanut-allergic children.
      (Table 2). Cross-reactivity has been reported to be mediated by Lup a 1 (vicilin-like protein)
      • Verma A.K.
      • Kumar S.
      • Das M.
      • Dwivedi P.D.
      A comprehensive review of legume allergy.
      ,
      • Moneret-Vautrin D.A.
      • Guérin L.
      • Kanny G.
      • Flabbee J.
      • Frémont S.
      • Morisset M.
      Cross-allergenicity of peanut and lupine: the risk of lupine allergy in patients allergic to peanuts.
      (Table 2). In 2017, the lupine profilin Lup a 5 was registered, which is highly cross-reactive to other profilins (eg, Ara h 5) and which is recognized by the sera of both lupine and peanut-allergic patients (www.allergome.org).

      Lipid Transfer Protein family

      Due to structural homology, lipd transfer proteings (LTPs) from different allergen sources are generally IgE cross-reactive; however, sensitization profiles are extremely heterogeneous, and individual cross-reactivity patterns may range from a single LTP to many different LTPs (from food or pollens).
      • Asero R.
      • Piantanida M.
      • Pinter E.
      • Pravettoni V.
      The clinical relevance of lipid transfer protein.
      ,
      • Egger M.
      • Hauser M.
      • Mari A.
      • Ferreira F.
      • Gadermaier G.
      The role of lipid transfer proteins in allergic diseases.
      Some studies report a significant number of peanut/TN allergies associated with LTP sensitization, which may be responsible for severe systemic reaction.
      • Zuidmeer L.
      • van Ree R.
      Lipid transfer protein allergy: primary food allergy or pollen/food syndrome in some cases.
      ,
      • Vereda A.
      • van Hage M.
      • Ahlstedt S.
      • et al.
      Peanut allergy: clinical and immunologic differences among patients from 3 different geographic regions.
      The peach LTP Pru p 3 has been shown to be the primary sensitizing allergen for cross-reactivity with other LTP, including peanut (Ara h 9), hazelnut (Cor a 8), walnut (Jug r 3), and almond (Pru du 3)
      • Mothes-Luksch N.
      • Raith M.
      • Stingl G.
      • et al.
      Pru p 3, a marker allergen for lipid transfer protein sensitization also in Central Europe.
      (Table 2). It has been shown that sensitization to LTP leads to a large variety of clinical manifestations; although oral allergy syndrome (OAS) is probably the most frequent clinical expression, LTPs can be also responsible for severe systemic reactions.
      • Egger M.
      • Hauser M.
      • Mari A.
      • Ferreira F.
      • Gadermaier G.
      The role of lipid transfer proteins in allergic diseases.
      ,
      • Zuidmeer L.
      • van Ree R.
      Lipid transfer protein allergy: primary food allergy or pollen/food syndrome in some cases.
      Thus, it is the most frequent cause of primary food allergy in the Mediterranean area.
      • Asero R.
      • Antonicelli L.
      • Arena A.
      • et al.
      EpidemAAITO: features of food allergy in Italian adults attending allergy clinics: a multi-centre study.
      ,
      • Flinterman A.E.
      • van Hoffen E.
      • den Hartog Jager C.F.
      • et al.
      Children with peanut allergy recognize predominantly Ara h2 and Ara h6, which remains stable over time.
      LTP sensitization can occur via the gastrointestinal tract, but the predominant presence of the LTP syndrome only in the Mediterranean region suggests that environmental factors play a major role. Indeed, Vereda et al showed that in peanut allergic patients, LTP sensitization rate varied by country: in Spain, 60% of patients are sensitized to peanut LTP (Ara h 9) while these proportions were 7.7% and 14.3% in the United States and in Sweden, respectively.
      • Vereda A.
      • van Hage M.
      • Ahlstedt S.
      • et al.
      Peanut allergy: clinical and immunologic differences among patients from 3 different geographic regions.
      The reasons for these geographical distributions are still poorly defined. Studies hypothesize that these distributions are in part due to variations in environmental homologous pollen allergens exposures in LTP-endemic areas such as Art v 3 from mugwort, or Pla a 3 from plane tree.
      • Asero R.
      • Piantanida M.
      • Pinter E.
      • Pravettoni V.
      The clinical relevance of lipid transfer protein.
      ,
      • Zuidmeer L.
      • van Ree R.
      Lipid transfer protein allergy: primary food allergy or pollen/food syndrome in some cases.
      In agreement with Pastorello,
      • Pastorello E.A.
      • Farioli L.
      • Pravettoni V.
      • et al.
      Pru p 3-sensitised Italian peach-allergic patients are less likely to develop severe symptoms when also presenting IgE antibodies to Pru p 1 and Pru p 4.
      Scala et al reported that, in LTP allergic patients, co-sensitization with PR-10 proteins, is associated with milder symptoms.. In addition, the higher the levels of birch pollen in a certain area, the lower the prevalence of LTP hypersensitivity.
      • Scala E.
      • Till S.J.
      • Asero R.
      • et al.
      Lipid transfer protein sensitization: reactivity profiles and clinical risk assessment in an Italian cohort.

      PR-10 family

      TN and peanut allergy may display serological as well as clinical cross-reactivity with pollens.
      • Uotila R.
      • Kukkonen A.K.
      • Pelkonen A.S.
      • Mäkelä M.J.
      Cross-sensitization profiles of edible nuts in a birch-endemic area.
      The majority of these patients suffer from OAS. Patients initially allergic to birch pollens through sensitization to a PR-10 protein, may develop a secondary allergy (pollen-food syndrome) to peanuts or TN (OAS);
      • Uotila R.
      • Kukkonen A.K.
      • Pelkonen A.S.
      • Mäkelä M.J.
      Cross-sensitization profiles of edible nuts in a birch-endemic area.
      ,
      • Price A.
      • Ramachandran S.
      • Smith G.P.
      • Stevenson M.L.
      • Pomeranz M.K.
      • Cohen D.E.
      Oral allergy syndrome (pollen-food allergy syndrome).
      they develop mainly mild symptoms limited to the oropharynx, with pruritus, tingling, erythema, and mild edema of the mouth upon ingestion of peanut or TNs(67). Pollen food syndrome (PFS) is triggered by a cross-reaction between allergens in pollen and allergens in peanuts/TN.
      • Uotila R.
      • Kukkonen A.K.
      • Pelkonen A.S.
      • Mäkelä M.J.
      Cross-sensitization profiles of edible nuts in a birch-endemic area.
      ,
      • Price A.
      • Ramachandran S.
      • Smith G.P.
      • Stevenson M.L.
      • Pomeranz M.K.
      • Cohen D.E.
      Oral allergy syndrome (pollen-food allergy syndrome).
      Homologous proteins have been identified between hazelnut, walnut, peanut, and soybean and have been shown to cross-react with Bet v 1.
      • Wangorsch A.
      • Jamin A.
      • Lidholm J.
      • et al.
      Identification and implication of an allergenic PR-10 protein from walnut in birch pollen associated walnut allergy.
      • Mittag D.
      • Akkerdaas J.
      • Ballmer-Weber B.K.
      • et al.
      Ara h 8, a Bet v 1-homologous allergen from peanut, is a major allergen in patients with combined birch pollen and peanut allergy.
      • Hofmann C.
      • Scheurer S.
      • Rost K.
      • et al.
      Cor a 1-reactive T cells and IgE are predominantly cross-reactive to Bet v 1 in patients with birch pollen-associated food allergy to hazelnut.
      The prevalence of PFS ranges from 4.7% to greater than 20% in children sensitized to pollens.
      • Price A.
      • Ramachandran S.
      • Smith G.P.
      • Stevenson M.L.
      • Pomeranz M.K.
      • Cohen D.E.
      Oral allergy syndrome (pollen-food allergy syndrome).
      ,
      • Carlson G.
      • Coop C.
      Pollen food allergy syndrome (PFAS): a review of current available literature.
      The PR-10 family also plays a significant role in PFS. Bet v 1 from birch pollen is well known of these proteins
      • Carlson G.
      • Coop C.
      Pollen food allergy syndrome (PFAS): a review of current available literature.
      and is one of the major pan-allergens in PFS.
      • Price A.
      • Ramachandran S.
      • Smith G.P.
      • Stevenson M.L.
      • Pomeranz M.K.
      • Cohen D.E.
      Oral allergy syndrome (pollen-food allergy syndrome).
      Uotila et al in a retrospective study found that among subjects with birch sensitization, 84% were cosensitized to hazelnut, 71% to almond, and 60% to peanut; amongst these nut-sensitized patients, 40% of patients sensitized to hazelnut, 34% of those sensitized to almond, and 36% of those sensitized to peanut reported typical symptoms of PFS.
      • Uotila R.
      • Kukkonen A.K.
      • Pelkonen A.S.
      • Mäkelä M.J.
      Cross-sensitization profiles of edible nuts in a birch-endemic area.
      A retrospective review from Northern France, where there is a high level of birch pollen exposure, reported a 43.2% co-existent TN allergy rate amongst patients with peanut allergy (43,2%), with hazelnut being the most common TN allergy observed.
      • Cousin M.
      • Verdun S.
      • Seynave M.
      • et al.
      Phenotypical characterization of peanut allergic children with differences in cross-allergy to tree nuts and other legumes.
      Symptoms associated with PR-10 sensitivity are mainly mild.
      • Mittag D.
      • Akkerdaas J.
      • Ballmer-Weber B.K.
      • et al.
      Ara h 8, a Bet v 1-homologous allergen from peanut, is a major allergen in patients with combined birch pollen and peanut allergy.
      ,
      • Kleine-Tebbe J.
      • Vogel L.
      • Crowell D.N.
      • Haustein U.-F.
      • Vieths S.
      Severe oral allergy syndrome and anaphylactic reactions caused by a Bet v 1- related PR-10 protein in soybean, SAM22.
      • Hansen K.S.
      • Ballmer-Weber B.K.
      • Lüttkopf D.
      • et al.
      Roasted hazelnuts--allergenic activity evaluated by double-blind, placebo-controlled food challenge.
      • Ortolani C.
      • Ballmer-Weber B.K.
      • Hansen K.S.
      • et al.
      Hazelnut allergy: a double-blind, placebo-controlled food challenge multicenter study.
      However, the thermostability of the proteins in this family are variable. Heat processing such as roasting significantly reduces the rosacea fruit protein allergenicity in patients with birch-pollen allergy, but some sensitized individuals can still experience positive reactivity toward roasted peanut, soy, and TNs.
      • Hansen K.S.
      • Ballmer-Weber B.K.
      • Lüttkopf D.
      • et al.
      Roasted hazelnuts--allergenic activity evaluated by double-blind, placebo-controlled food challenge.

      Diagnostics for peanut and tree nut allergy

      Peanut and TN allergy is typically diagnosed based on a combination of a convincing history of a IgE mediated allergic reaction, SPT, serum-specific IgE and, if necessary, an OFC.
      • Sicherer S.H.
      • Sampson H.A.
      Food allergy: a review and update on epidemiology, pathogenesis, diagnosis, prevention, and management.
      • Boyce J.A.
      • Assa’ad A.
      • Burks A.W.
      • Jones S.M.
      • Sampson H.A.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel.
      • Burks A.W.
      • Jones S.M.
      • Boyce J.A.
      • et al.
      NIAID-sponsored 2010 guidelines for managing food allergy: applications in the pediatric population.
      • Sampson H.A.
      • Aceves S.
      • Bock S.A.
      • et al.
      Food allergy: a practice parameter update—2014.
      For example, peanut allergy is diagnosed based on the clinical history of reaction, the presence of risk factors (severe atopic dermatitis) and if needed additional tests such as SPT, sIgE, and component resolved diagnosis (CRD). Although the cut-off points for determining allergy vary in different regions/clinical settings, these tests have led to a major improvement of the diagnosis of peanut allergy. If history and allergy tests are discordant, the gold standard for diagnosis of food allergies is the double-blind, placebo-controlled, food challenge (DBPCFC).
      • Matricardi P.M.
      • Kleine-Tebbe J.
      • Hoffmann H.J.
      • et al.
      EAACI molecular allergology user's guide.
      One of the major issues in clinical practice is the difficulty in distinguishing asymptomatic sensitization (false positives) from primary allergy and from secondary allergy (PFS); this is particularly complex for nut allergies due to the high prevalence of pollen co-sensitization.
      • Weinberger T.
      • Sicherer S.
      Current perspectives on tree nut allergy: a review.

      Double-blind, placebo-controlled, food challenge

      Although the DBPCFC is the gold standard for diagnosis of food allergies, this is costly, resource and time-consuming, and carries the risk of potentially life-threatening reactions. Some patients or their parents refuse to perform an OFC due to the fear of triggering a severe reaction. In the Pronuts study, Brough et al reported that 8.2% of children did not perform an OFC due to fear of reaction or history of previous severe reaction on exposure to the incriminated nut.
      • Brough H.A.
      • Caubet J.-C.
      • Mazon A.
      • et al.
      Defining challenge-proven coexistent nut and sesame seed allergy: a prospective multicenter European study.
      In this clinical setting, not performing an OFC can potentially lead to unnecessary and prolonged peanut/TN avoidance, which may have the unintended risk of increasing peanut/TN allergy risk.
      • McWilliam V.L.
      • Perrett K.P.
      • Dang T.
      • Peters R.L.
      Prevalence and natural history of tree nut allergy.
      However, it is necessary to find new, less invasive diagnostic tools for the diagnosis of peanuts/TN allergies. Studies have shown that combination of SPT, sIgE, and basophil activation test (BAT) improved the ability to identify allergic and tolerant patients. In the case of peanut allergic patients, this approach could potentially lead to a reduction of OFC of 76.6%–97%.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      ,
      • Santos A.F.
      • Douiri A.
      • Bécares N.
      • et al.
      Basophil activation test discriminates between allergy and tolerance in peanut-sensitized children.

      SPT and specific IgE to whole extract allergen

      As for other allergies, it is of major importance to interpret peanut/TN SPT and sIgE in the context of the clinical history. The diagnostic value of SPT and specific IgE to whole allergen extracts has been found to vary significantly among studies. Indeed, those different results might be explained by differences in the population studied, prevalence of pollen allergy, and the methodology used in the study.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      ,
      • Uotila R.
      • Kukkonen A.K.
      • Pelkonen A.S.
      • Mäkelä M.J.
      Cross-sensitization profiles of edible nuts in a birch-endemic area.
      ,
      • Eigenmann P.A.
      • Sampson H.A.
      Interpreting skin prick tests in the evaluation of food allergy in children.
      ,
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      Clinical and molecular characterization of walnut and pecan allergy (NUT CRACKER study).
      These data have been summarized in Table 3. As an example, while a SPT <3 mm has a good negative predictive value;
      • Randhawa I.
      • Morphew T.
      • Marsteller N.L.
      Correlation of negative skin-prick test results for tree nuts and successful tree nut challenges among children with peanut allergy.
      • Stiefel G.
      • Anagnostou K.
      • Boyle R.J.
      • et al.
      BSACI guideline for the diagnosis and management of peanut and tree nut allergy.
      • Sampson H.
      Comparative study of commercial food antigen extracts for the diagnosis of food hypersensitivity.
      • Sporik R.
      • Hill D.J.
      • Hosking C.S.
      Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children. Clinical <html_ent glyph="@amp;" ascii=.
      SPT<3 mm still requires further investigations in the context of a convincing clinical history of nut allergy. In contrast, a SPT ≥3 mm to a specific nut, without an appropriate clinical context has a poor predictive value and is associated with high rate of false positives.
      • Stiefel G.
      • Anagnostou K.
      • Boyle R.J.
      • et al.
      BSACI guideline for the diagnosis and management of peanut and tree nut allergy.
      ,
      • Rancé F.
      • Abbal M.
      • Lauwers-Cancès V.
      Improved screening for peanut allergy by the combined use of skin prick tests and specific IgE assays.
      ,
      • Eigenmann P.A.
      • Sicherer S.H.
      • Borkowski T.A.
      • Cohen B.A.
      • Sampson H.A.
      Prevalence of IgE-mediated food allergy among children with atopic dermatitis.
      Clark et al showed that amongst patients with a history of reaction to peanut or TN, a SPT ≥8 mm had a predicted clinical reactivity greater than 95% accuracy.
      • Clark A.T.
      • Ewan P.W.
      Interpretation of tests for nut allergy in one thousand patients, in relation to allergy or tolerance. Clinical <html_ent glyph="@amp;" ascii=.
      Ho et al confirmed this threshold value for cashew, hazelnut, and walnut.
      • Ho M.
      • Heine R.
      • Wong W.
      • Hill D.
      Diagnostic accuracy of skin prick testing in children with tree nut allergy.
      Table 3
      FoodCutoffs for sIgE to extract allergenCutoffs for specific IgE to main componentsCutoffs for specific skin prick test
      Peanut≥15 kU/L, 95% PPV
      • Sampson H.A.
      Utility of food-specific IgE concentrations in predicting symptomatic food allergy.
      • Sicherer S.H.
      • Morrow E.H.
      • Sampson H.A.
      Dose-response in double-blind, placebo-controlled oral food challenges in children with atopic dermatitis.
      • Perry T.T.
      • Matsui E.C.
      • Conover-Walker M.K.
      • Wood R.A.
      Risk of oral food challenges.
      ≥4 mm–15mm, 95%–100% PPV
      • Stiefel G.
      • Anagnostou K.
      • Boyle R.J.
      • et al.
      BSACI guideline for the diagnosis and management of peanut and tree nut allergy.
      Ara h 2 sIgE: 0.35–42.2 kU/L had 90%–95% PPV
      • Santos A.F.
      • Douiri A.
      • Bécares N.
      • et al.
      Basophil activation test discriminates between allergy and tolerance in peanut-sensitized children.
      ,
      • Beyer K.
      • Grabenhenrich L.
      • Härtl M.
      • et al.
      Predictive values of component-specific IgE for the outcome of peanut and hazelnut food challenges in children.
      ,
      • Nicolaou N.
      • Poorafshar M.
      • Murray C.
      • et al.
      Allergy or tolerance in children sensitized to peanut: prevalence and differentiation using component-resolved diagnostics.
      ,
      • Nicolaou N.
      • Murray C.
      • Belgrave D.
      • Poorafshar M.
      • Simpson A.
      • Custovic A.
      Quantification of specific IgE to whole peanut extract and peanut components in prediction of peanut allergy.
      • Bernard H.
      • Paty E.
      • Mondoulet L.
      • et al.
      Serological characteristics of peanut allergy in children.
      • Klemans R.J.B.
      • van Os-Medendorp H.
      • Blankestijn M.
      • Bruijnzeel-Koomen C.A.F.M.
      • Knol E.F.
      • Knulst A.C.
      Diagnostic accuracy of specific IgE to components in diagnosing peanut allergy: a systematic review.
      • Lieberman J.A.
      • Glaumann S.
      • Batelson S.
      • Borres M.P.
      • Sampson H.A.
      • Nilsson C.
      The utility of peanut components in the diagnosis of IgE-mediated peanut allergy among distinct populations.
      Arah 8 : 0.6 kU/L to 100 kU/L
      • Mittag D.
      • Akkerdaas J.
      • Ballmer-Weber B.K.
      • et al.
      Ara h 8, a Bet v 1-homologous allergen from peanut, is a major allergen in patients with combined birch pollen and peanut allergy.
      Arah 9: no available values
      Hazelnut≥0,7kU/L- 15 kU/L or greater 57%-92%PPV
      • Ortolani C.
      • Ballmer-Weber B.K.
      • Hansen K.S.
      • et al.
      Hazelnut allergy: a double-blind, placebo-controlled food challenge multicenter study.
      ,
      • Masthoff L.J.N.
      • Mattsson L.
      • Zuidmeer-Jongejan L.
      • et al.
      Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults.
      ≥8 mm–17mm or greater, 74%-100%PPV
      • Ho M.
      • Heine R.
      • Wong W.
      • Hill D.
      Diagnostic accuracy of skin prick testing in children with tree nut allergy.
      ,
      • Masthoff L.J.
      • Pasmans S.G.
      • Hoffen E.
      • et al.
      Diagnostic value of hazelnut allergy tests including rCor a 1 spiking in double-blind challenged children.
      ≤0,35kU/l, 95%NVP
      • Masthoff L.J.N.
      • Mattsson L.
      • Zuidmeer-Jongejan L.
      • et al.
      Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults.
      Cor a 9 sIgE: 1 kU/L had 83% accuracy
      • Masthoff L.J.N.
      • Mattsson L.
      • Zuidmeer-Jongejan L.
      • et al.
      Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults.
      Cor a 14 sIgE: 0.72–47.8 kU/L had 87%–90% accuracy
      • Beyer K.
      • Grabenhenrich L.
      • Härtl M.
      • et al.
      Predictive values of component-specific IgE for the outcome of peanut and hazelnut food challenges in children.
      ,
      • Kattan J.D.
      • Sicherer S.H.
      • Sampson H.A.
      Clinical reactivity to hazelnut may be better identified by component testing than traditional testing methods.
      Cor a 1: no available values
      Cor a 8: no available values
      Walnut≥5.07 kU/L −18,5kU/L or greater, 95%–99% PPV
      • Maloney J.M.
      • Rudengren M.
      • Ahlstedt S.
      • Bock S.A.
      • Sampson H.A.
      The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.
      ,
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      Clinical and molecular characterization of walnut and pecan allergy (NUT CRACKER study).
      ≥8 mm, 95%PPV
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      ,
      • Ho M.
      • Heine R.
      • Wong W.
      • Hill D.
      Diagnostic accuracy of skin prick testing in children with tree nut allergy.
      Jug r 1 sIgE: 0.1 kU/L had 91% PPV(113), ≥0,35kU/l, accuracy 0,93(81)
      Jugr 4 ≥ 0,35kU/L, accuracy 0,93(81)
      Jug r 3: no available values
      Pecan≥7 mm, 75% PPV
      • Ho M.
      • Heine R.
      • Wong W.
      • Hill D.
      Diagnostic accuracy of skin prick testing in children with tree nut allergy.
      Cashew≥8 kU/l – 149.5kU/L or greater: 95%PPV
      • Ho M.
      • Heine R.
      • Wong W.
      • Hill D.
      Diagnostic accuracy of skin prick testing in children with tree nut allergy.
      ,
      • Inoue Y.
      • Trapnell B.C.
      • Tazawa R.
      • et al.
      Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan.
      ≥8 mm, 95%PPV
      • Ho M.
      • Heine R.
      • Wong W.
      • Hill D.
      Diagnostic accuracy of skin prick testing in children with tree nut allergy.
      ≥10–12 mm, 95% PPV
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      ,
      • McWilliam V.
      • Peters R.L.
      • Allen K.J.
      • et al.
      Skin prick test predictive values for the outcome of cashew challenges in children.
      Ana o 3 sIgE: 0.16 kU/L had 97.1% accuracy for cashew and/or pistachio nut allergy
      • Savvatianos S.
      • Konstantinopoulos A.P.
      • Å Borgå
      • et al.
      Sensitization to cashew nut 2S albumin, Ana o 3, is highly predictive of cashew and pistachio allergy in Greek children.
      Pistachio≥88 kU/l, 90% accuracy
      • Maloney J.M.
      • Rudengren M.
      • Ahlstedt S.
      • Bock S.A.
      • Sampson H.A.
      The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.
      Almond
      Pru du 1 (PR-10)
      Brazil nut≥3,5kU/l 100% PPV
      • Ridout S.
      • Matthews S.
      • Gant C.
      • Twiselton R.
      • Dean T.
      • Arshad S.H.
      The diagnosis of Brazil nut allergy using history, skin prick tests, serum-specific immunoglobulin E and food challenges.
      ≥6 mm, PPV 100%
      • Ridout S.
      • Matthews S.
      • Gant C.
      • Twiselton R.
      • Dean T.
      • Arshad S.H.
      The diagnosis of Brazil nut allergy using history, skin prick tests, serum-specific immunoglobulin E and food challenges.
      ≥9 mm, accuracy ≥95%
      • Clark A.T.
      • Ewan P.W.
      Interpretation of tests for nut allergy in one thousand patients, in relation to allergy or tolerance. Clinical <html_ent glyph="@amp;" ascii=.
      Ber e 1 sIgE: 0.25 kU/L had 94% PPV
      • Rayes H.
      • Raza A.A.
      • Williams A.
      • Matthews S.
      • Arshad S.H.
      Specific IgE to recombinant protein (Ber e 1) for the diagnosis of Brazil nut allergy.
      PPV: positive predictive value, NPV: negative predictive value, PR-10: Pathogenesis related protein type 10.
      Specific IgE to whole allergen extracts of peanut/TN are more widely available than SPTs and improve the management of patients with a suspicion of nut allergy. However, similarly to SPT, there is a large variation regarding the reported diagnostic values of sIgE.
      • Maloney J.M.
      • Rudengren M.
      • Ahlstedt S.
      • Bock S.A.
      • Sampson H.A.
      The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy.
      ,
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      ,
      • Baker M.G.
      • Kattan J.D.
      Review of 400 consecutive oral food challenges to almond.
      • Ridout S.
      • Matthews S.
      • Gant C.
      • Twiselton R.
      • Dean T.
      • Arshad S.H.
      The diagnosis of Brazil nut allergy using history, skin prick tests, serum-specific immunoglobulin E and food challenges.
      • Ortolani C.
      • Ballmer-Weber B.K.
      • Hansen K.S.
      • et al.
      Hazelnut allergy: a double-blind, placebo-controlled food challenge multicenter study.
      Data are summarized in Table 3. As an example, Sampson et al showed in the 1990s that a peanut sIgE ≥15kU/L could predict clinical reactivity with greater than 95% certainty.
      • Sampson H.A.
      • Ho D.G.
      Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents☆☆☆★.
      Clark et al confirmed and extended this result to TN allergy.
      • Clark A.T.
      • Ewan P.W.
      Interpretation of tests for nut allergy in one thousand patients, in relation to allergy or tolerance. Clinical <html_ent glyph="@amp;" ascii=.
      ,
      • Du Toit G.
      • Santos A.
      • Roberts G.
      • Fox A.T.
      • Smith P.
      • Lack G.
      The diagnosis of IgE-mediated food allergy in childhood.
      Fleisher et al reported that only 63% of patients with a history of clinical TN allergy and TN sIgE levels <2 kU/L passed their OFC.
      • Fleischer D.M.
      • Conover-Walker M.K.
      • Matsui E.C.
      • Wood R.A.
      The natural history of tree nut allergy.
      In a retrospective study, Couch et al reported a higher proportion of patients with a negative OFC (89%) with similar levels of sIgE (<2kU/L).
      • Couch C.
      • Franxman T.
      • Greenhawt M.
      Characteristics of tree nut challenges in tree nut allergic and tree nut sensitized individuals.
      Specific IgE and SPT are routinely performed as a first-line procedure to support the diagnosis of allergy; however, false negatives can occur. These false negatives can be explained in part by the fact that commercial extracts (SPT and sIgE) do not contain extracts of oleosins (lipid-bound allergens) that are responsible for some allergic reactions. Modified skin prick testing (using the actual nut or nut butter), or the use of CRD to measure oleosins (e.g Ara h 10 and 11 for peanut) or in the basophilic activation test would therefore be valuable diagnostic tools, but these data need to be confirmed by further studies.
      • Jappe U.
      • Schwager C.
      Relevance of lipophilic allergens in food allergy diagnosis.

      Component resolved diagnosis

      During the last decade, the introduction of CRD has led to a major improvement in the diagnosis of nut allergies.
      • Weinberger T.
      • Sicherer S.
      Current perspectives on tree nut allergy: a review.
      ,
      • McWilliam V.L.
      • Perrett K.P.
      • Dang T.
      • Peters R.L.
      Prevalence and natural history of tree nut allergy.
      ,
      • Treudler R.
      • Simon J.C.
      Overview of component resolved diagnostics.
      It is now possible to identify patients who have developed sIgE against seed storage proteins that are associated with a high risk of systemic reactions. The most well-known example is sIgE to Ara h 2, which is a peanut seed storage protein. It has been shown that 80%–100% of patients with primary peanut allergy are sensitized to Ara h 2.
      • Flinterman A.E.
      • van Hoffen E.
      • den Hartog Jager C.F.
      • et al.
      Children with peanut allergy recognize predominantly Ara h2 and Ara h6, which remains stable over time.
      ,
      • Koppelman S.J.
      • Wensing M.
      • Ertmann M.
      • Knulst A.C.
      • Knol E.F.
      Relevance of Ara h1, Ara h2 and Ara h3 in peanut-allergic patients, as determined by immunoglobulin E Western blotting, basophil-histamine release and intracutaneous testing: Ara h2 is the most important peanut allergen.
      • Beyer K.
      • Grabenhenrich L.
      • Härtl M.
      • et al.
      Predictive values of component-specific IgE for the outcome of peanut and hazelnut food challenges in children.
      • Nicolaou N.
      • Poorafshar M.
      • Murray C.
      • et al.
      Allergy or tolerance in children sensitized to peanut: prevalence and differentiation using component-resolved diagnostics.
      • Dang T.D.
      • Tang M.
      • Choo S.
      • et al.
      Increasing the accuracy of peanut allergy diagnosis by using Ara h 2.
      Cut-off decision points for Ara h 2 sIgE have been determined in multiple studies, but there is a large variation of the reported values (Table 3). Hazelnut also contains seed storage proteins, ie, Cor a 9 and Cor a 14, and sIgE to these proteins have also been associated with systemic reactions.
      • Beyer K.
      • Grishina G.
      • Bardina L.
      • Grishin A.
      • Sampson H.A.
      Identification of an 11S globulin as a major hazelnut food allergen in hazelnut-induced systemic reactions.
      ,
      • Masthoff L.J.N.
      • Mattsson L.
      • Zuidmeer-Jongejan L.
      • et al.
      Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults.
      These tests have been found to be highly specific and more sensitive than sIgE and SPT to whole allergen extract to diagnose a primary hazelnut allergy.
      • Beyer K.
      • Grishina G.
      • Bardina L.
      • Grishin A.
      • Sampson H.A.
      Identification of an 11S globulin as a major hazelnut food allergen in hazelnut-induced systemic reactions.
      However, there is again a large variation of reported diagnostic values, particularly for sIgE to Cor a 14.
      • Beyer K.
      • Grabenhenrich L.
      • Härtl M.
      • et al.
      Predictive values of component-specific IgE for the outcome of peanut and hazelnut food challenges in children.
      ,
      • Beyer K.
      • Grishina G.
      • Bardina L.
      • Grishin A.
      • Sampson H.A.
      Identification of an 11S globulin as a major hazelnut food allergen in hazelnut-induced systemic reactions.
      • Masthoff L.J.N.
      • Mattsson L.
      • Zuidmeer-Jongejan L.
      • et al.
      Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults.
      • Kattan J.D.
      • Sicherer S.H.
      • Sampson H.A.
      Clinical reactivity to hazelnut may be better identified by component testing than traditional testing methods.
      • Eller E.
      • Mortz C.G.
      • Bindslev-Jensen C.
      Cor a 14 is the superior serological marker for hazelnut allergy in children, independent of concomitant peanut allergy.
      • Faber M.A.
      • De Graag M.
      • Van Der Heijden C.
      • et al.
      Cor a 14: missing link in the molecular diagnosis of hazelnut allergy?.
      • Buyuktiryaki B.
      • Cavkaytar O.
      • Sahiner U.M.
      • et al.
      Cor a 14, hazelnut-specific IgE, and SPT as a reliable tool in hazelnut allergy diagnosis in eastern mediterranean children.
      In addition, some studies have highlighted specific factors affecting the variation of the diagnostic values of sIgE to Cor a 9 and Cor a 14. Particularly, the age of the child may affect the diagnostic value of these tests. Thus, it has been found that Cor a 9-sIgE specificity decreases with age, while Cor a 14-sIgE specificity increases with age.
      • Masthoff L.J.N.
      • Mattsson L.
      • Zuidmeer-Jongejan L.
      • et al.
      Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults.
      ,
      • Santos A.F.
      • Brough H.A.
      Making the most of in vitro tests to diagnose food allergy.
      ,
      • De Knop K.J.
      • Verweij M.M.
      • Grimmelikhuijsen M.
      • et al.
      Age-related sensitization profiles for hazelnut (Corylus avellana) in a birch-endemic region: hazelnut allergy: sensitization profiles.
      Specific IgE to seed storage proteins found in other TNs (ie, Jug r 1, Jug r 4 in walnut or Ana o 3 in cashew nut) have also been found to improve diagnostic accuracy of allergy to these nuts.
      • Savvatianos S.
      • Konstantinopoulos A.P.
      • Å Borgå
      • et al.
      Sensitization to cashew nut 2S albumin, Ana o 3, is highly predictive of cashew and pistachio allergy in Greek children.
      • Costa J.
      • Carrapatoso I.
      • Oliveira M.B.P.P.
      • Mafra I.
      Walnut allergens: molecular characterization, detection and clinical relevance.
      • Sordet C.
      • Culerrier R.
      • Granier C.
      • et al.
      Expression of Jug r 1, the 2S albumin allergen from walnut (Juglans regia), as a correctly folded and functional recombinant protein.
      • Robotham J.M.
      • Teuber S.S.
      • Sathe S.K.
      • Roux K.H.
      Linear IgE epitope mapping of the English walnut (Juglans regia ) major food allergen, Jug r 1.
      Regarding walnut, sIgE to Jug r 1 and Jug r 4, were reported to provide the best distinction between walnut allergy and sensitization.
      • Blankestijn M.A.
      • Blom W.M.
      • Otten H.G.
      • et al.
      Specific IgE to Jug r 1 has no additional value compared with extract-based testing in diagnosing walnut allergy in adults.
      ,
      • Sato S.
      • Yamamoto M.
      • Yanagida N.
      • et al.
      Jug r 1 sensitization is important in walnut-allergic children and youth.
      Indeed, sIgE to Jug r 1 and Jug r 4 have been found to be positive in 75% and in 56.7–66% of walnut allergic patients, respectively.
      • Mew R.
      • Borres M.
      • Sjölander S.
      • du Toit G.
      A retrospect study into the utility of allergen components in walnut allergy.
      ,
      • Wallowitz M.
      • Peterson W.R.
      • Uratsu S.
      • Comstock S.S.
      • Dandekar A.M.
      • Teuber S.S.
      Jug r 4, a legumin group food allergen from walnut ( Juglans regia cv. Chandler).
      The NutCracker study found that IgE levels ≥0.35kU/L to Jug r 1 and Jug r 4 provided the best diagnosis method for identifying walnut allergic patients (accuracy 0,93) (Table 3). In addition, the NutCracker study reported that patients with walnut and pecan dual allergy were more frequently sensitized to Jug r 4 compared to patients with isolated walnut allergy.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      Clinical and molecular characterization of walnut and pecan allergy (NUT CRACKER study).
      Regarding cashew nut, 2 European studies have shown that up to 93% of children with cashew allergy are sensitized to Ana o 3.
      • Savvatianos S.
      • Konstantinopoulos A.P.
      • Å Borgå
      • et al.
      Sensitization to cashew nut 2S albumin, Ana o 3, is highly predictive of cashew and pistachio allergy in Greek children.
      ,
      • Lange L.
      • Lasota L.
      • Finger A.
      • et al.
      Ana o 3-specific IgE is a good predictor for clinically relevant cashew allergy in children.
      Ana o 3 sIgE level ≥0.16kU/L had 97.1% accuracy for cashew and/or pistachio nut allergy.
      • Savvatianos S.
      • Konstantinopoulos A.P.
      • Å Borgå
      • et al.
      Sensitization to cashew nut 2S albumin, Ana o 3, is highly predictive of cashew and pistachio allergy in Greek children.
      ,
      • Lange L.
      • Lasota L.
      • Finger A.
      • et al.
      Ana o 3-specific IgE is a good predictor for clinically relevant cashew allergy in children.
      ,
      • Reitsma M.
      • Bastiaan-Net S.
      • Sforza S.
      • et al.
      Purification and characterization of Anacardium occidentale (cashew) allergens Ana o 1, Ana o 2, and Ana o 3.
      (Table 3). Specific IgE to Ana o 3 have been reported as a highly accurate diagnosis marker also for pistachio allergy.
      • Geiselhart S.
      • Hoffmann-Sommergruber K.
      • Bublin M.
      Tree nut allergens.
      ,
      • Savvatianos S.
      • Konstantinopoulos A.P.
      • Å Borgå
      • et al.
      Sensitization to cashew nut 2S albumin, Ana o 3, is highly predictive of cashew and pistachio allergy in Greek children.
      Peanut/TN allergies may be the expression of a sensitization to LTP family (eg, Arah 9, Cor a 8, Jug r 3). Hazelnut has received the most extensive evaluation. Studies reported that sensitization to a hazelnut LTP (eg, Cor a 8) is a risk factor for objective symptoms in children from a Mediterranean region.
      • Flinterman A.E.
      • Akkerdaas J.H.
      • den Hartog Jager C.F.
      • et al.
      Lipid transfer protein-linked hazelnut allergy in children from a non-Mediterranean birch-endemic area.
      • Schocker F.
      • Lüttkopf D.
      • Scheurer S.
      • et al.
      Recombinant lipid transfer protein Cor a 8 from hazelnut: a new tool for in vitro diagnosis of potentially severe hazelnut allergy.
      • Pastorello E.A.
      • Vieths S.
      • Pravettoni V.
      • et al.
      Identification of hazelnut major allergens in sensitive patients with positive double-blind, placebo-controlled food challenge results.
      Hansen et al, in a multicenter study performed in Switzerland, Spain, and Denmark, reported that amongst patients with hazelnut allergy, 28% had positive sIgE to rCor a 8. The highest rate of sensitization to the LTP rCor a 8 was reported in Spain (71%), followed by Switzerland (15%), then Denmark (5%). LTP sensitization was present in 5 out of 7 patients (71%) with severe symptoms to hazelnut and in 11 out of 52 patients (21%) with milder reactions.
      • Hansen K.S.
      • Ballmer-Weber B.K.
      • Sastre J.
      • et al.
      Component-resolved in vitro diagnosis of hazelnut allergy in Europe.
      Diagnostic values of sIgE vary significantly between studies and cut-offs have not been clearly established. There are many confounding factors such as pollen influences, patterns of sensitization (food or pollen) and geographic distribution.
      Distinction between primary and secondary allergy is a challenge and use of CRD can help differentiate phenotypes of peanut/TN allergy and co-sensitization. Uotila et al found that in a birch pollen endemic region, patients with peanut sensitization without associated symptoms and peanut allergic patients were equally sensitized to PR-10 proteins (Bet v 1 90%). In this cohort, over 90% avoided TNs but only 6%–44% presented with specific sensitizations to seed storage protein to TNs.
      • Uotila R.
      • Kukkonen A.K.
      • Blom W.M.
      • et al.
      Component-resolved diagnostics demonstrates that most peanut-allergic individuals could potentially introduce tree nuts to their diet.
      Hence, an accurate diagnosis based on CRD might have helped to decrease the rate of unnecessary avoidance. Proteins of the PR-10 family have been identified for walnut (Jug r 5),
      • Costa J.
      • Carrapatoso I.
      • Oliveira M.B.P.P.
      • Mafra I.
      Walnut allergens: molecular characterization, detection and clinical relevance.
      hazelnut (Cor a 1),
      • Hirschwehr R.
      • Valenta R.
      • Ebner C.
      • et al.
      Identification of common allergenic structures in hazel pollen and hazelnuts: a possible explanation for sensitivity to hazelnuts in patients allergic to tree pollen.
      almond (Pru du 1),
      • Costa J.
      • Mafra I.
      • Carrapatoso I.
      • Oliveira M.B.P.P.
      Almond allergens: molecular characterization, detection, and clinical relevance.
      and peanut (Ara h 8).
      • Mittag D.
      • Akkerdaas J.
      • Ballmer-Weber B.K.
      • et al.
      Ara h 8, a Bet v 1-homologous allergen from peanut, is a major allergen in patients with combined birch pollen and peanut allergy.
      As with primary allergies, the clinical expression of sensitization to PR-10 might be dependant on the specific IgE levels.
      • Webber C.M.
      • England R.W.
      Oral allergy syndrome: a clinical, diagnostic, and therapeutic challenge.

      Basophil activation test

      The BAT is another promising diagnostic tool for nut allergy.
      • Wasserman R.L.
      • Hague A.R.
      • Pence D.M.
      • et al.
      Real-world experience with peanut oral immunotherapy: lessons learned from 270 patients.
      ,
      • Scala E.
      • Till S.J.
      • Asero R.
      • et al.
      Lipid transfer protein sensitization: reactivity profiles and clinical risk assessment in an Italian cohort.
      This test is not yet largely available in the clinical setting, because it requires appropriate equipment and trained personnel. Thus, Santos et al proposed to restrict the use of BAT to selected cases, for which the results of routinely used tests do not allow a precise diagnosis.
      • Santos A.F.
      • Douiri A.
      • Bécares N.
      • et al.
      Basophil activation test discriminates between allergy and tolerance in peanut-sensitized children.
      Several studies reported that in the diagnosis of peanut/TN allergies, BAT had a sensitivity ranging between 81.3% and 98%, and a specificity ranging between 77 and 100%.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      ,
      • Santos A.F.
      • Brough H.A.
      Making the most of in vitro tests to diagnose food allergy.
      ,
      • Hoffmann H.J.
      • Santos A.F.
      • Mayorga C.
      • et al.
      The clinical utility of basophil activation testing in diagnosis and monitoring of allergic disease.
      However, cut-offs determined for the BAT can vary according to the population studied, the design of the study, and the methodology adopted for the BAT procedure and data analyses.
      • Santos A.F.
      • Douiri A.
      • Bécares N.
      • et al.
      Basophil activation test discriminates between allergy and tolerance in peanut-sensitized children.
      Regarding peanut allergy, Santos et al and Ocmant et al determined optimal cut-off points for CD63 at 4.78% and 9.1%, respectively.
      • Santos A.F.
      • Douiri A.
      • Bécares N.
      • et al.
      Basophil activation test discriminates between allergy and tolerance in peanut-sensitized children.
      ,
      • Ocmant A.
      • Mulier S.
      • Hanssens L.
      • et al.
      Basophil activation tests for the diagnosis of food allergy in children.
      Basophil reactivity in peanut-allergic subjects was found to be associated with the severity of allergic reaction, and it has also been shown that BATs may be useful in monitoring patients undergoing OIT.
      • Ocmant A.
      • Mulier S.
      • Hanssens L.
      • et al.
      Basophil activation tests for the diagnosis of food allergy in children.
      • Jones S.M.
      • Pons L.
      • Roberts J.L.
      • et al.
      Clinical efficacy and immune regulation with peanut oral immunotherapy.
      • Thyagarajan A.
      • Jones S.M.
      • Calatroni A.
      • et al.
      Evidence of pathway-specific basophil anergy induced by peanut oral immunotherapy in peanut-allergic children.
      However, studies are still needed to confirm these results.
      Studies evaluating the diagnostic value of the BAT for TN allergy are limited. Regarding hazelnut allergy, it has been found that the BAT has a sensitivity ranging between 85% and 100% and specificity ranging between 80% and 97%.
      • Hoffmann H.J.
      • Santos A.F.
      • Mayorga C.
      • et al.
      The clinical utility of basophil activation testing in diagnosis and monitoring of allergic disease.
      ,
      • Erdmann S.M.
      • Heussen N.
      • Moll-Slodowy S.
      • Merk H.F.
      • Sachs B.
      CD63 expression on basophils as a tool for the diagnosis of pollen-associated food allergy: sensitivity and specificity.
      • Brandström J.
      • Nopp A.
      • Johansson S.G.O.
      • et al.
      Basophil allergen threshold sensitivity and component-resolved diagnostics improve hazelnut allergy diagnosis.
      • Lötzsch B.
      • Dölle S.
      • Vieths S.
      • Worm M.
      Exploratory analysis of CD63 and CD203c expression in basophils from hazelnut sensitized and allergic individuals.
      Recently, it was suggested that the use of the BAT in combination with SPT was useful for the diagnosis of TN allergies. Preliminary results report that the combination of BAT with SPT and clinical co-existent allergy knowledge enable the differentiation of co-allergenicity patterns in patients sensitized to walnut, pecan, cashew and pistachio.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      NUT Co reactivity - ACquiring knowledge for elimination recommendations (NUT CRACKER) study.
      However, these data should be examined in a prospective study with a larger patient population. In addition, BAT has been also shown to be potentially useful in identifying the culprit allergen in cases of PFS.
      • Erdmann S.M.
      • Heussen N.
      • Moll-Slodowy S.
      • Merk H.F.
      • Sachs B.
      CD63 expression on basophils as a tool for the diagnosis of pollen-associated food allergy: sensitivity and specificity.
      ,
      • Glaumann S.
      • Nopp A.
      • Johansson S.G.O.
      • Rudengren M.
      • Borres M.P.
      • Nilsson C.
      Basophil allergen threshold sensitivity, CD-sens, IgE-sensitization and DBPCFC in peanut-sensitized children: CD-sens, IgE-ab and peanut allergy.
      • Wölbing F.
      • Kunz J.
      • Kempf W.E.
      • Grimmel C.
      • Fischer J.
      • Biedermann T.
      The clinical relevance of birch pollen profilin cross-reactivity in sensitized patients.
      • Mayorga C.
      • Gomez F.
      • Aranda A.
      • et al.
      Basophil response to peanut allergens in Mediterranean peanut-allergic patients.

      Management

      The basic approach to peanut/TN allergy management does not defer from current management approaches to other food allergies. It includes short-term, immediate treatment of symptoms after the exposure and long-term strategies assuring strict avoidance of culprit nut and minimising risk of any future reactions.
      • Muraro A.
      • Werfel T.
      • Hoffmann-Sommergruber K.
      • et al.
      EAACI Food Allergy and Anaphylaxis Guidelines: diagnosis and management of food allergy.
      The management of mild reactions has been based on the same therapies for many years, namely non-sedating antihistamines.
      • Anagnostou K.
      • Swan K.E.
      • Brough H.
      The use of antihistamines in children.
      Epinephrine is the cornerstone and first-line treatment for anaphylaxis.
      • Shaker M.S.
      • Wallace D.V.
      • Golden D.B.K.
      • et al.
      Anaphylaxis—a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis.
      Early recognition of signs of anaphylaxis and prompt administration of epinephrine are absolutely key, and patients with potential anaphylaxis to peanut/TN should have easy access to epinephrine autoinjectors in the community.
      Improved understanding of the pathophysiological mechanisms involved in allergic reactions may give rise to additional useful treatments. Vadas et al reported on the role of PAF and the activity of PAF acethylhydrolase in anaphylactic reactions.
      • Vadas P.
      • Gold M.
      • Perelman B.
      • et al.
      Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis.
      Arias et al, in an experimental study in peanut-sensitized mice, reported that PAF antagonists significantly decrease the duration and severity of the anaphylactic reaction compared to other therapeutics (histamine receptor antagonist, 5 lipooxygenase inhibitor). Indeed 83% of PAF-treated versus 43% of untreated mice reached recovery within 120 min after peanut challenge. In addition, they also report that the combination of PAF receptor antagonists and histamine receptor antagonists allows for better management and an even more significant reduction in the severity and duration of the reaction.
      • Arias K.
      • Baig M.
      • Colangelo M.
      • et al.
      Concurrent blockade of platelet-activating factor and histamine prevents life-threatening peanut-induced anaphylactic reactions.
      Long-term strategies assuring avoidance of index nut are quite complex and require a multidisciplinary approach, involving good education of patients and their families. This education involves teaching parents and their children to read food labels and recognise their allergen appropriately. Identifying and clearly listing the most common food allergens has become a legal requirement in many countries, but practices differ throughout the world. Many food companies also choose to add Precautionary Allergen Labels (PAL), such as “may contain”, but it is not always clear what these labels mean, and consumers often do not fully understand this.
      • Hourihane J.O.
      • Dean T.P.
      • Warner J.O.
      Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges.
      Historically, the main management approach to nut allergy was strict, blanket avoidance of all nuts in all peanut and TN allergic patients. Although avoiding all nuts simplifies the management and may decrease the risk of reactions secondary to cross-contact or misidentification, it has many pitfalls. As peanut/TN are long-term allergies, patients must avoid all nuts (ie,. peanuts and TN) even if they might be clinically tolerant to selective nuts, which puts an additional and unnecessary restriction on patients’ diet and social activities, which in turn reduces quality of life
      • Avery N.J.
      • King R.M.
      • Knight S.
      • Hourihane J.O.
      Assessment of quality of life in children with peanut allergy.
      and increases anxiety levels.
      • King R.M.
      • Knibb R.C.
      • Hourihane J.O.
      Impact of peanut allergy on quality of life, stress and anxiety in the family.
      Strict avoidance of all nuts may lead to development of new allergies, as well as nutritional consequences, and influence growth, particularly in children with other food allergies.
      • Elizur A.
      • Bollyky J.B.
      • Block W.M.
      Elimination diet and the development of multiple tree-nut allergies: this work was done as part of Dr. Elizur's sabbatical from Sackler School of Medicine, Tel Aviv University, Israel.
      ,
      • Flammarion S.
      • Santos C.
      • Guimber D.
      • et al.
      Diet and nutritional status of children with food allergies.
      • Brough H.A.
      • Turner P.J.
      • Wright T.
      • et al.
      Dietary management of peanut and tree nut allergy: what exactly should patients avoid?.
      • Christie L.
      • Hine R.J.
      • Parker J.G.
      • Burks W.
      Food allergies in children affect nutrient intake and growth.
      On the other hand, introducing selective nuts in the diet of patients allergic to some types of nuts can be complicated, requires multiple investigations, and often multiple in-hospital OFCs, which are limited not only by the available resources and time, but also carry risk, as reactions occurring during these OFCs can be severe.
      • Brough H.A.
      • Caubet J.-C.
      • Mazon A.
      • et al.
      Defining challenge-proven coexistent nut and sesame seed allergy: a prospective multicenter European study.
      Another important safety aspect of selective nut consumption is patients' and their families’ ability to correctly recognise and distinguish the correct nuts themselves. A study involving 1105 participants conducted by Hostetler et al investigated the ability of children and adults to appropriately identify peanut/TNs. Participants were shown 19 different pictures of peanuts and TNs, and the mean number of correct responses was only 8.4. There was a significant difference between children and adults, but parents with nut allergic children did not perform any better than parents of children without a known nut allergy.
      • Hostetler T.L.
      • Hostetler S.G.
      • Phillips G.
      • Martin B.L.
      The ability of adults and children to visually identify peanuts and tree nuts.
      Healthcare professionals' approach to the matter of nut avoidance in peanut/TN allergies management has changed; patient populations and their preferences have also changed. Patients and their families prefer having more freedom in making choices and tend to get more involved in their management decisions and wish dietary restriction to have less repercussions on their daily life. Management of their peanut/TN allergies should be tailored to each patient, taking into consideration many aspects in addition to test results, such as age, history of previous reactions, concomitant conditions, patients' and families’ understanding of their allergies, tendency towards risk taking, anxiety level, quality of life, and ultimately, what our patients and their families want as part of shared decision making.
      • Anagnostou A.
      • Hourihane J.O.
      • Greenhawt M.
      The role of shared decision making in pediatric food allergy management.
      Building up immune tolerance in mainly peanut but also TN allergies has been a major focus of food allergy research over the past decade. The number of double-blind placebo controlled trials (with several trials including large numbers of participants) investigating oral, sublingual, and epicutaneous routes have showed this treatment approach to be efficacious in desensitizing the individual (increasing their threshold dose of reactivity), with quite a good safety profile.
      • Blumchen K.
      • Trendelenburg V.
      • Ahrens F.
      • et al.
      Efficacy, safety, and quality of life in a multicenter, randomized, placebo-controlled trial of low-dose peanut oral immunotherapy in children with peanut allergy.
      • Fink W.R.
      • Capucilli P.
      • Lewis M.O.
      • Rooney C.B.
      • Brown-Whitehorn T.F.
      Significantly increased threshold dose after long-term peanut epicutaneous immunotherapy and daily oral peanut intake.
      • Vickery B.P.
      • Vereda A.
      • Casale T.B.
      • Beyer K.
      • du Toit G.
      • et al.
      PALISADE Group of Clinical Investigators
      AR101 oral immunotherapy for peanut allergy.
      However, the question of safety of different routes of peanut/TN immunotherapy and the benefit/risk ratio of this type of treatment remains a concern. A systematic review and meta-analysis published by Chu. et al showed that patients undergoing peanut oral immunotherapy (OIT) had a significant increase in anaphylaxis risk and frequency.
      • Chu D.K.
      • Wood R.A.
      • French S.
      • et al.
      Oral immunotherapy for peanut allergy (PACE): a systematic review and meta-analysis of efficacy and safety.
      Authors concluded that peanut OIT achieved a modest degree of desensitization but caused more allergic and anaphylactic reactions in participants receiving treatment with peanut (albeit mostly during the updosing phase in hospital), when compared with the placebo group. On the other hand, as much as other routes such as epicutaneous or sublingual might have a better safety profile, they might not be as effective as the oral route.
      • Fleischer D.M.
      • Greenhawt M.
      • Sussman G.
      • et al.
      Effect of epicutaneous immunotherapy vs placebo on reaction to peanut protein ingestion among children with peanut allergy: the PEPITES randomized clinical trial.
      This question will not be answered accurately unless large double-blind multiple arm studies comparing different routes of peanut/TN immunotherapy are performed.
      Another approach to TN OIT would be using nut clusters such as cashew/pistachio,
      • Brough H.A.
      • Caubet J.-C.
      • Mazon A.
      • et al.
      Defining challenge-proven coexistent nut and sesame seed allergy: a prospective multicenter European study.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      Walnut oral immunotherapy for desensitisation of walnut and additional tree nut allergies (Nut CRACKER): a single-centre, prospective cohort study.
      walnut/pecan,
      • Brough H.A.
      • Caubet J.-C.
      • Mazon A.
      • et al.
      Defining challenge-proven coexistent nut and sesame seed allergy: a prospective multicenter European study.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      Walnut oral immunotherapy for desensitisation of walnut and additional tree nut allergies (Nut CRACKER): a single-centre, prospective cohort study.
      and pecan/walnut/hazelnut/macadamia nuts
      • Brough H.A.
      • Caubet J.-C.
      • Mazon A.
      • et al.
      Defining challenge-proven coexistent nut and sesame seed allergy: a prospective multicenter European study.
      as a treatment approach. Indeed, Elizur et al showed in their open label study investigating efficacy of walnut oral immunotherapy in 73 participants in which 55 participants received active treatment, all children with co-existing pecan allergy were also desensitised to pecan and 93% of children who were co-allergic to hazelnut were desensitised after their course of OIT with walnut.
      • Elizur A.
      • Appel M.Y.
      • Nachshon L.
      • et al.
      Walnut oral immunotherapy for desensitisation of walnut and additional tree nut allergies (Nut CRACKER): a single-centre, prospective cohort study.
      Although these results seem promising, there is a lack of substantial evidence, and this might be quite an interesting and large area for future research.
      Lastly, the question of TN allergy prevention still remains open. There is quite substantial evidence for the early introduction of peanuts being protective against development of peanut allergy in high risk infants. The LEAP (Learning Early About Peanut Allergy)randomised controlled trial showed a relative reduction in school-aged peanut allergy prevalence of 86.1% in peanut skin prick test negative and 70% in skin prick positive infants who started eating peanuts by the age of 11 months, when compared with the group who avoided peanut.
      • Du Toit G.
      • Roberts G.
      • Sayre P.H.
      • et al.
      Randomized trial of peanut consumption in infants at risk for peanut allergy.
      This finding was sequentially supported by the results from the EAT (Enquiring about tolerance) study in the per protocol group and in children with positive sIgE >0.1kU/L.
      • Perkin M.R.
      • Logan K.
      • Bahnson H.T.
      • et al.
      Efficacy of the Enquiring about Tolerance (EAT) study among infants at high risk of developing food allergy.
      ,
      • Perkin M.R.
      • Logan K.
      • Tseng A.
      • et al.
      Randomized trial of introduction of allergenic foods in breast-fed infants.
      In addition, as the follow up LEAP-On Study showed, this protective effect remained beyond time of intervention, and 1 year of peanut avoidance was not associated with an increase in peanut allergy.
      • Du Toit G.
      • Sayre P.H.
      • Roberts G.
      • et al.
      Effect of avoidance on peanut allergy after early peanut consumption.