WHEAT ALLERGY, A NEW AND EMERGING THREAT OF FOOD ALLERGY FOR CHILDREN

WHEAT ALLERGY, A NEW AND EMERGING THREAT OF FOOD ALLERGY FOR CHILDREN | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Pediatric Allergy and Immunology This is a preprint and has not been peer reviewed. Data may be preliminary. 4 July 2025 V1 Latest version Share on WHEAT ALLERGY, A NEW AND EMERGING THREAT OF FOOD ALLERGY FOR CHILDREN Authors : Pakit Vichyanond 0000-0001-5103-2916 [email protected] , Ken-ichi Nagakura , Punchama Pacharn 0000-0002-2507-2057 , Gary Wong 0000-0001-5939-812X , and Hugh Sampson 0000-0003-1613-8875 Authors Info & Affiliations https://doi.org/10.22541/au.175163044.43564416/v1 Published Pediatric Allergy and Immunology Version of record Peer review timeline 602 views 317 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Compared to cow’s milk, eggs and peanut, knowledge on wheat allergy is limited. During the past 2 decades, IgE-mediated wheat allergy in children is frequently observed all over the World, especially in Asia. Wheat allergy usually presents in infants between 6-12 months of age. Common clinical manifestation is skin rash (maculopapular rash, urticaria and angioedema). Atopic dermatitis is a less common preceding manifestation in wheat allergy compared to egg and cow’s milk allergy. Anaphylaxis occurs in up to 50% of wheat allergy in children. Wheat-dependent, exercise-induced anaphylaxis is more common among older children, teenagers and adults. Skin prick test with water-soluble extract of wheat gave low diagnostic sensitivity. This is because major wheat allergens are alcohol-soluble proteins. Specific IgE to components of wheat such as ω-5 gliadin could increase diagnostic accuracy. The use of these component-resolved wheat allergens both in singleplex and multiplex tests are available but accuracy of these tests remains to be verified. Wheat avoidance is difficult to carry out since wheat is used for cooking in wide varieties of daily diets. Oral immunotherapy to wheat has been extensively investigated over the past 15 years among children with varying degree of wheat sensitivities. Most of these children achieved some degree of desensitization to wheat but only few attained sustained unresponsiveness. To date, it is unclear how long wheat oral immunotherapy should be maintained. Recently, an outbreak in Japan on allergy to soap containing hydrolyzed-wheat suggested that route of sensitization of wheat was through skin. Discontinuation of marketing of this soap led to cessation of such epidemic. Such knowledge warrants further investigation in children so that a prevention measure for wheat allergy among high-risk infants can be designed. WHEAT ALLERGY, A NEW AND EMERGING THREAT OF FOOD ALLERGY FOR CHILDREN Pakit Vichyanond, MD 1, Ken-Ichi Nagakura, MD, PhD 2 Punchama Pacharn, MD 1 Gary Wong, MD, PhD 3 Hugh A Sampson, MD 4 1. Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok Thailand 2. Department of Pediatrics, National Hospital Organization Sagamihara National Hospital, Kanagawa, Japan 3. Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong. Hong Kong, China 4. Division of Allergy and Immunology, Department of Pediatrics, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York Total pages: 37; Figures 3; Table -1- References 85 Total word count: 6641, Line count - 543 Correspondence : Emeritus Professor Pakit Vichyanond MD Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Rd, Kwang Siriraj, Khet Bangkoknoi, Bangkok 10700 Telephone: 66-81-407-1589; E-mail: [email protected] Key words: wheat allergy, anaphylaxis, oral food challenge, oral immunotherapy, ω-5 gliadin. Role of authors: Pakit Vichyanond: Conceptualizing, major collaborator, writing, editing, reviewing. Ken-Ichi Nagakura: Section author, editing, reviewing Punchama Pacharn: Section author, editing and reviewing Gary Wong: Conceptualizing, editing and reviewing Hugh A Sampson: Conceptualizing, editing, review and supervising Conflict of interest: HAS reports grants from Immune Tolerance Network; NIAID/NIH, and the Food Allergy Research & Education (FARE), and personal fees from N-Fold LLC and DBV Technologies, Alpina Biotech AG, RAPT Therapeutics and Siolta Therapeutics. Other authors report no conflict of interest. Abbreviation ATI – amylase/trypsin inhibitor BAT – basophil activation test ED – eliciting dose EIARD – exercise-induced, allergic reaction on desensitization FEIA - fluorescence enzyme immunoassay MAT – mast cell activation test HMW – high-molecular weight LMW – low-molecular weight OIT – oral immunotherapy sIgE – specific IgE SPT- skin prick test SU – sustained unresponsiveness WADA – wheat anaphylaxis dependent on augmentation WDEIA = wheat-dependent, exercise-induced anaphylaxis WOIT – wheat oral immunotherapy ABSTRACT Compared to cow’s milk, eggs and peanut, knowledge on wheat allergy is limited. During the past 2 decades, IgE-mediated wheat allergy in children is frequently observed all over the World, especially in Asia. Wheat allergy usually presents in infants between 6-12 months of age. Common clinical manifestation is skin rash (maculopapular rash, urticaria and angioedema). Atopic dermatitis is a less common preceding manifestation in wheat allergy compared to egg and cow’s milk allergy. Anaphylaxis occurs in up to 50% of wheat allergy in children. Wheat-dependent, exercise-induced anaphylaxis is more common among older children, teenagers and adults. Skin prick test with water-soluble extract of wheat gave low diagnostic sensitivity. This is because major wheat allergens are alcohol-soluble proteins. Specific IgE to components of wheat such as ω-5 gliadin could increase diagnostic accuracy. The use of these component-resolved wheat allergens both in singleplex and multiplex tests are available but accuracy of these tests remains to be verified. Wheat avoidance is difficult to carry out since wheat is used for cooking in wide varieties of daily diets. Oral immunotherapy to wheat has been extensively investigated over the past 15 years among children with varying degree of wheat sensitivities. Most of these children achieved some degree of desensitization to wheat but only few attained sustained unresponsiveness. To date, it is unclear how long wheat oral immunotherapy should be maintained. Recently, an outbreak in Japan on allergy to soap containing hydrolyzed-wheat suggested that route of sensitization of wheat was through skin. Discontinuation of marketing of this soap led to cessation of such epidemic. Such knowledge warrants further investigation in children so that a prevention measure for wheat allergy among high-risk infants can be designed. Key message: IgE-mediated wheat allergy including anaphylaxis from wheat has been increasing observed worldwide. The study on hydrolyzed wheat allergy from Japan suggested that percutaneous absorption could be the route for sensitization to wheat in adults. Whether this is true in children and what would be sources of wheat allergens in the environment remains to be clarified. SPT to commercial wheat allergens yields low diagnostic sensitivity and specificity. Further diagnostic tests such as CRD, epitope-specific sIgE, BAT and MAT to wheat allergens have been studied but their utility need to be further explored prior for use in general allergy practices. Oral immunotherapy to wheat either via conventional or low-dose OIT is efficacious in the treatment for immediate wheat allergy. Appropriate duration for wheat OIT to induce sustained unresponsiveness is not yet known but perhaps would need a longer period than in OITs for peanut and egg. INTRODUCTION: Food allergy in childhood is increasingly observed worldwide (1, 2) . The leading foods responsible for causing allergic reaction in children are cow’s milk, eggs and peanuts. However, recent reports from Asian countries such as Japan (3),Thailand (4) and Korea (5) indicated that wheat allergy is becoming more recognized among referred pediatric allergy centers. For example, wheat was the third most common cause of food anaphylaxis in a national food registry from Japan (6). In a retrospective study of food anaphylaxis from an academic center from Thailand, wheat anaphylaxis was observed to be as high as 50% (4) whereas rate of wheat anaphylaxis in a Japanese report was 10% (3). Interestingly, a large prospective cohort study from Singapore indicated that wheat allergy was not a common event (7). Such discrepancy in prevalence suggested that differences in feeding practices and environmental factors in early life could be play a significant role in the development of wheat allergy. Wheat sensitization is a usual finding among infants with atopic dermatitis in the United States and Europe (8, 9). In contrast, generalized urticaria, facial edema and anaphylaxis were common presenting features of wheat allergic children in Asia (3, 4). . Aside from immediate IgE-mediated allergic reaction, wheat has been reported to be a culprit for non IgE-mediated food allergy such as food-protein induced proctocolitis and food-protein induced enterocolitis (10, 11). In adults, wheat-dependent, exercise-induced anaphylaxis (WDEIA) has long been a recognizable syndrome and has been thoroughly investigated (12, 13). WDEIA can also occurred in children as a presenting symptom of wheat allergy (14) and as a complication seen after oral immunotherapy (OIT) with wheat (15). Wheat is also responsible of myriad of other immunologic mediated disorders such as Baker’s asthma, celiac disease. Therefore, adverse immunologic response to wheat could be diverse and is responsible to various clinical presentations, outcomes with different prognosis. It is the objective of this paper to update pediatric allergists with the current knowledge of wheat allergy in children. We will concentrate only with spectrum of IgE-mediated wheat allergy in this review. WHEAT AND ITS ALLERGENS: Wheat (Triticum) belongs to a group wild grass which has been cultivated for domestication since 9600 BC, with its origin possibly locating in region of West Asia, perhaps in a part of Turkey (16). During this long period of cultivation, varieties of cultivars developed including common wheat (Triticum aestivum), spelt, durum, durum, Emmett and Khorasan or Kamut. Seed is the major part yielding nutrients for consumption, including varieties of carbohydrates (fiber, starch) and proteins. Wheat is a major source of vegetable proteins accounting to about 13% of its weight. Wheat protein is known to be relatively lack of lysine. Seed of wheat is the major source of carbohydrate and protein localizing in the endosperm - major food supply for the embryo-germ of wheat grain (Figure 1). Seeds are milled to separate out outer part (bran) to produce wheat flour. Major protein from wheat flour, through increasing in water and kneading, create a group protein designated as ‘gluten’ primarily comprising gliadins (alpha, beta and gamma gliadins) and glutenins (low molecular weight – LMW and high molecular weight - HMW glutenins). Gluten is alcohol soluble (not water-salt soluble) and is responsible for most IgE-mediated reactions (see text below). Other proteins from wheat include water-salt soluble fragments such of albumins and globulins with amylase/trypsin inhibitor (ATI’s) being the most recognizable allergen in Baker’s asthma. Among all wheat protein allergens, ω-5 gliadin has been the most extensively studied. ω-5 gliadin (Tri a 19, MW 65 kDa) was identified to be the major allergen responsible for WDEIA in both children and adults (12, 17). . Kennard et al recently proposed that WDEIA in adults should be referred to as ω-5 gliadin allergy (12). However, among wheat allergic children, sIgE to omega-5 gliadin could be found in sera from both wheat-allergic and wheat-tolerant children. Ebisawa et al, suggested to include sIgE to both whole wheat allergens and to 5-omega gliadin to improve the prediction of wheat allergy in children (3). sIgEs to other wheat allergens to both salt-soluble and alcohol-soluble fractions was present in sera of wheat allergic children (18-20). For example, a study by Nilsson from Sweden clearly showed that in challenge positive children, sIgEs to ω -5 gliadin was present as well as sIgE to LMW and HMW glutenins (18). Sievers, et al from Germany also observed similar findings and concluded that microarray study to wheat epitopes might not be productive in predicting wheat allergy (19). In a study from Thailand by Rootrakul et al, examined sIgEs to various wheat allergens using SDS-immunoblot assay. A wide range of positive bands to both glutenins and gliadins were found among challenged positive children both with high and low wheat sIgE (20). Proteins in the non-gluten (salt-soluble protein) such as ATI’s (Tri a 15) was found to be associated with Baker’s asthma but was not well studied in IgE-mediated disease (21). Modification of food proteins from cooking and hydrolysation could produce neoallergens from foods, The most striking example of modified allergens from wheat was in an epidemic of WDEIA and even frank anaphylaxis among Japanese (mainly women) who had used soap contained hydrolyzed wheat (22). Immunoblots of sera from these patients against hydrolysed wheat extract showed unusual patterns of reactions with bands occupying a wide range of molecular weight (23). Hydrolyzation of wheat could results in new wheat allergens due to deamidation process. Cessation of this hydrolyzed-wheat-protein allergy by elimination of hydrolyzed wheat-containing soap from the Japanese market supported the notion that the syndrome was caused by hydrolyzed wheat (23). This syndrome also suggested that wheat sensitization could occur through skin and could occur in adults. EPIDEMIOLOGY AND CLINICAL PRESENTATIONS: In spite of the fact that IgE-mediated wheat allergy has been reported throughout the World, there has been a discrepancy in its prevalence in different parts of the World. In a recent meta-analysis on prevalence of wheat allergy by Liu et al (24), point prevalence of wheat allergy ranged from 0.04% (by food challenge) to 0.6% (self-reported). Among self-reported prevalence from this study, adults reported higher prevalence than in children (0.83% vs 0.58%). Developed economic nations reported higher prevalence than developing economic nations (0.62% vs 0.46%) and reports from African countries showed the highest prevalence (1.33%) followed by from those from Southeast Asian countries (1.12%). There was a trend for small decreasing prevalence over time. Perspectives from Asia (PV and KN), indicated that wheat allergy has been increasing observed in tertiary allergy centers over the past 15 years. However, this has not been statistically confirmed. In China, wheat allergy was common among city in northern China such as in Tianjin city where prevalence of wheat allergy among children 1-3 years of age was reported to be as high as 22% (25). Surprisingly, wheat allergy in Singapore and Hong Kong was less frequently reported (7, 26). This suggests that differences in wheat prevalence could be due to different cultural and environmental practices (such as feeding routines) rather than due to ethnic differences. Wheat allergy in adults primarily presents as wheat-dependent, exercise-induced anaphylaxis (WDEIA). Kennard et al from England reported a large cohort of adults n = 13 2) with WDEIA (12). In this report, there were more males than females (60% vs 40%) with age of presentation ranged from 40-50 years. Anaphylaxis was of severe grade and delay in diagnosis was common (1-5 years from the beginning of the disease to the time of diagnosis). Exercise was the most common cofactor (80%) followed by alcohol ingestion (25%) and intake of NSAID (9%). Since exercise was not a consistent co-factor for the development of this ‘ω -5 allergy’, Brockow recently suggested the terminology of w heat a naphylaxis d ependent on a ugmentation (WADA)’ to be used instead of WDEIA (17). Most children with wheat allergy present with urticaria and angioedema, particularly in the periorbital region (see Figure 2a). Among a large cohort of Japanese wheat allergic children as reported by Ebisawa et al, skin manifestations was observed in 100% of cases (3). Respiratory symptoms (nasal discharge, cough and wheeze) was observed in 30%; gastrointestinal symptoms (abdominal pain, vomiting) in 10% and anaphylaxis in 10% of cases (3). In a report of wheat allergy in 100 Thai children, anaphylaxis was observed in 50% of cases with another 50% presented with skin manifestations only (4). Median age of presentation were 40 months old (compared to 2.3 years among the Japanese children). Age of onset of symptoms among the Thai children was 6-7 months and most developed symptoms after the first bite of wheat-containing foods (mostly bread). Atopic dermatitis was observed in 59% of the skin-only group while only 35% of the anaphylaxis had this comorbidity. Although sIgE to omega-5 gliadin was higher among cases with anaphylaxis in both studies, no clear cut-off could clearly define anaphylaxis from non-anaphylactic group. With oral wheat challenge, it was demonstrated that wheat anaphylaxis could also occur in children with low level of sIgE (20). WDEIA can be a primary presentation of wheat allergy in older children and teenagers (27); although this is less frequently observed than in adults population. Severe symptoms involving cardiovascular and respiratory system were observed in most of these children (Figure 2B). Localized urticaria appeared only anterior abdominal wall upon wheat challenge (without systemic manifestation) was reported among children with low sIgE – see Figure 2C. Such syndrome has been coined ‘localized abdominal urticarial (LAU)’ (28). Such skin reaction spontaneous resolved in most cases. Diagnostic tests for wheat allergy 4.1 Skin prick test (SPT) SPT is the most commonly used method in evaluation of IgE-mediated wheat allergy. However, predictive accuracy of SPTs varies significantly depending on the type of extracts used. In a systematic review and meta-analysis, a commercial wheat extract (cut-off 3 mm wheal) exhibited low-moderate diagnostic accuracy (53% sensitivity, 72% specificity) (29). In contrast, an in-house Coca–10% ethanol (EtOH) extract demonstrated a superior diagnostic performance (91.7% sensitivity, 66.7% specificity), likely due to the enhanced solubility of gliadin (a major wheat allergen) in alcohol (30). In a cohort of 31 children, a gliadin extract yielded a sensitivity of 84.2% and an accuracy of 85.7%, surpassing the diagnostic performance of a commercial wheat extract (sensitivity 55%, accuracy 65.5% (31). Furthermore, gliadin extract remained stable for up to 12 months at 2–8°C, supporting its long-term clinical utility (32). However, these in-house extracts are not widely available, limiting their global applicability. For WDEIA, few studies have evaluated the diagnostic accuracy of the SPT. Commercial wheat extracts used in SPT exhibited limited sensitivity. One study reported positive results in 94% and 100% of patients using prick-to-prick testing with wheat flour and gluten, respectively. However, only half of the patients tested positive for commercial wheat extract (33). In another study, an in-house Coca–10% EtOH extract reported positive SPT results in 12 of 14 patients, emphasizing the importance of alcohol-based extracts for detecting allergens in WDEIA (34). 4.2 Specific IgE (sIgE) to wheat extract The sIgE testing is widely accessible, but its diagnostic accuracy for wheat allergy diagnosis varies across studies. Moreover, each study employed different cut-off points. A high cut-off point can achieve a specificity. Sampson and Ho from the US using a cut-off point of 26 kU A /L to wheat provided 92% specificity, but the sensitivity was only 61% (35). In the study by Nilsson et al, using 70 kU A /L as a cut-off point provided 97% specificity and 62% sensitivity (18). A study from Japan used 10.1 kU A /L as a cut-off point found specificity to be 74% and sensitivity of 61% (3). However, each of these studies represents a “discovery set,” and no “testing set” was analyzed for validation. Consequently, this raises a question about the “generalizability” of their findings. A recent systematic review and meta-analysis by Riggioni et al showed the sIgE level to wheat of 0.6 kU A /L to be the optimal cut-off, providing 72% sensitivity and 79% specificity (29). Although 0.35 kU A /L confers higher sensitivity (96-100%), its specificity is poor (20-50%) (30, 35). Therefore, no conclusion can be made about certain values of wheat sIgE in predicting positive wheat challenges. Allergists should therefore strongly consider confirming wheat allergy by oral food challenges, especially in uncertain cases with relatively low sIgE levels and uncertain allergy history. 4.3 Component-resolved diagnosis (CRD) Wheat-allergic patients react to widely different wheat allergens, depending on their clinical symptoms. In immediate wheat allergy and WDEIA, ω-5-gliadin has been reported as a major wheat allergen (3, 36). As a result, the diagnosis of WDEIA may be overlooked if clinicians rely exclusively on wheat-sIgE. One study of 47 challenge-positive WDEIA found wheat-sIgE positivity in 78.7% of cases, which increased to 91.5% when ω-5-gliadin-sIgE was used (36). For immediate wheat allergy, a European study found that some wheat-allergic patients react to water-soluble allergens and, therefore, require a test capable of detecting multiple components to make the diagnosis (37). Additional allergens, including α, β and γ-gliadins, have also been reported as major allergens in children and adults with wheat allergy in Thailand (20, 35). However, identification of relevant allergens in immediate wheat allergy requires further studies. Therefore, it is not agreeable on which wheat allergens (beside ω-5-gliadin) to be included in the test panel to improve the diagnosis of wheat allergy. CRD, by multiplex methods can document more elaborated IgE reactions to wheat allergens. The FEIA immunoCAP ® assay provides a limited panel, including. gluten, ω-5-gliadin (Tri a 19), and non-specific lipid transfer protein (ns-LTP, Tri a 14). Compared with wheat-sIgE, ω-5-gliadin-sIgE offers a higher diagnostic precision (3, 30). Similar to wheat-sIgE, various cut-off points have been reported for diagnosing immediate wheat allergy. In a study from Japan, a cut-off of 0.41 kU A /L for ω-5-gliadin-sIgE yielded 72% sensitivity and 79% specificity, whereas wheat-sIgE yielded 61% sensitivity and 74% specificity (3). Another study from Thailand showed that a cut-off of 0.1 kU A /L for ω-5-gliadin-sIgE provided 83.3% sensitivity and 83.3% specificity (30). A systematic review and meta-analysis recently identified 0.3 kU A /L as the optimal cut-off point for ω-5-gliadin-sIgE, yielding 79% sensitivity and 78% specificity (29). Again, these studies report “discovery data” and require validation to support generalizability of results. Multiplex assays, such as Immuno CAP® ISAC™ (Thermo Fisher Scientific Inc.) and the ELISA-based macroarray immunoassay (ALEX®, MacroArray Diagnostics, Vienna, Austria), can detect Tri a 19, Tri a 14, and Tri a aA_TI only without measuring sIgE to wheat crude extract. In addition, the data for diagnosing wheat allergy by these two techniques remain limited (38, 39). Another study using an in-house semi quantitative microarray assay found no significant difference in diagnostic capacity between wheat-sIgE and ω-5-gliadin-sIgE with ImmunoCAP, yet diagnostic accuracy improved with the microarray technique, particularly when more than five components tested positive (40). This enhanced diagnostic yield may be due to the inclusion of additional wheat allergens (e.g., α-, β-, γ-gliadin) and water-soluble allergens such as alpha-amylase inhibitors (AAI) the microarray assay. Basophil and mast cell activation test (BAT and MAT) Flow cytometry assays that measure activation markers on basophils (the basophil activation test, BAT) and mast cells (the mast cell activation test, MAT) serve as alternative methods for diagnosing food allergies. These tests demonstrate a high specificity and sensitivity in peanut and sesame allergy (41), although up to 10% - 15%% of patients may be basophil non-responders and were not included in these results. However, the use of BAT for wheat allergy diagnosis is limited. For wheat allergy, a study of 58 children with suspected wheat allergy found that native omega-5-gliadin (nOG5)-induced CD203c^high% values most effectively distinguished wheat allergy from tolerance, yielding a sensitivity of 85.0% and specificity of 77.0% at a 14.4% cut-off (42). Additionally, %CD63^+ basophil levels show good diagnostic utility in differentiating patients with WDEIA from control groups (43, 44). However, this study requires validation, and these tests are not widely available, excepted for only in research settings. Evidence for MAT in food allergy diagnosis, especially wheat allergy, remains limited. In a study of 30 patients with wheat allergy, sera from individuals with atopic eczema induced degranulation in response to albumin/globulin extracts, whereas among those with WDEIA or anaphylaxis, half of the sera reacted to low-molecular-weight (LMW) glutenin but rarely tested positive for lipid transfer protein (43). Further studies are needed to standardize and validate these methods and assess their feasibility for routine practice. 4.5 Epitope-specific (es) Antibodies The Bead-Based Epitope Assay (BBEA) is a Luminex-based platform designed to quantify multiple epitope-specific antibodies simultaneously, encompassing the IgE, IgG, IgA, and IgD isotypes. It is a good tool to predict clinical reactivity and differentiate phenotypes of food allergies (45, 46). The BBEA was shown to effectively diagnose and distinguish clinical phenotypes in 122 pediatric and adolescent patients (83 wheat-allergic, 39 wheat-tolerant) (47). Machine learning identified epitope-specific IgE (es-IgE) as the most informative markers for diagnosing wheat allergy. Higher es-IgE binding intensity, reflecting higher es-IgE antibody levels, correlated with more severe phenotypes. In contrast, WDEIA showed lower es-IgG1 binding intensity than all the other groups. Four informative epitopes particularly ω-5-gliadin and γ-gliadin were the best predictors for wheat allergy, with an area under the curve of 0.908 (sensitivity = 83.4% and specificity = 88.4%). 4.6 Oral food challenge test (OFC) The OFC remains the gold standard for diagnosing wheat allergy. In addition, it is recommended to establish the reaction threshold (eliciting dose) before starting oral immunotherapy. The AAAI-EAACI PRACTALL guidelines recommend the semi-logarithmic dosing protocol (48). A starting dose of 1 mg or 3 mg of wheat protein is commonly used in research settings and for high-risk patients. In one study, an initial 3 mg dose triggered 67% of grade III reactions A study on wheat oral immunotherapy reported a median ED of 13 mg of wheat protein in complicated cases. A 5-dose regimen that combines the first three doses into 43 mg of wheat protein can be used for individuals who are not expected to react to a low dose (48). The final portion of challenge food depends on the age of patients. For wheat OFC, the portion size is ¼ to 2 slices of bread (48). Beyond diagnosing wheat allergy, OFCs also help determine remission and establish the maximum tolerated dose before starting oral immunotherapy. Since WDEIA can be life threatening, a definitive diagnosis of WDEIA by OFC is often critical in managing such patients. However, the clinical reproducibility of wheat OFC for WDEIA is low. The positivity rate of challenge tests ranges from 50% to 100%, depending on the protocol used (49). Typically, testing requires 3 to 4 days, encompassing separate phases of wheat alone, exercise alone, and a combined food and exercise challenge (49). Adding cofactors such as aspirin along with exercise increases the likelihood of positive results but could also lower the threshold for reactions and heightens severity, whereas alcohol yields ambiguous outcomes (50). In one pediatric study combining aspirin, exercise, and wheat ingestion, four of 14 patients experienced severe anaphylaxis (Brown grade III) (14). Therefore, introducing cofactors into the challenge test can improve diagnostic accuracy but increase the risk of severe reactions, necessitating careful consideration, particularly for patients with a history of severe anaphylaxis. An alternative method to reduce severity involves using gluten for challenge without exercise. The percentages of a positive challenge to gluten at rest were 36.6%-48% (37, 50). These patients also react after exercise, but with a lower threshold and increased severity. Given safety considerations, an initial gluten challenge at rest is recommended; if negative, an exercise-based OFC incorporating additional cofactors may then be undertaken. Interestingly, a study tracking patients with WDEIA who adopted different eating habits, i.e., complete avoidance of wheat versus consumption with a four-hour restriction before or after exercise showed interesting results. OFCs performed one month later revealed that the reaction threshold decreased in patients who strictly avoided wheat but increased in those who maintained wheat intake under the four-hour restriction. These findings underscore the need for individualized dietary guidance to optimize patient outcomes (51). Therefore, in diagnosing wheat allergy, one should begin by assessing pre-test probability through clinical history, symptom timing, and potential cofactors. Subsequent testings, such as SPT and sIgE, are then performed and interpreted together with the initial probability estimate. Ambiguous or high-risk cases often require OFC for definitive diagnosis. By integrating clinical likelihood, test results, and patient factors, such structured approach maximizes diagnostic accuracy and enhances patient safety. Treatment of wheat allergy 5.1 Wheat avoidance As indicated earlier, anaphylaxis can be frequently observed among wheat allergic children (3, 4). In a nationwide survey of Japanese nursery schools, wheat was the third most common cause of food anaphylaxis (8%, n = 3,661) in children with food allergies (n = 5,806) (6). Moreover, accidental wheat exposure still occurred despite stringent avoidance measures. Six out of 9 American children with wheat allergy experienced accidental ingestions during a one-year follow-up period (52). In a larger group of Japanese children with wheat allergy who were followed during Covid-19 outbreak, 12 of 138 children (8.7%) accidentally ingested wheat resulting in 2 episodes of anaphylaxis (1.4%) indicating that accidental exposure could still occur despite epidemic restriction (53). Wheat avoidance, as with other food allergies, is the treatment of choice for wheat allergic patients. However, wheat avoidance is difficult to accomplish in daily life. Wheat is the main source of energy (carbohydrate and protein) in form of daily staple particularly in bread, pasta and noodles (yellow noodles, udon, soba), In addition, due to its intrinsic viscoelastic properties, wheat is added to other foods during cooking to increase taste and palatability (Maillard’s reaction), to retain form, shape and crispiness of foods. For instance, wheat is an essential component of pork and fish balls to retain the shape and crisp feeling upon chewing. Additionally, wheat flour is commonly chosen to replace rice flour in several common recipes in the Eastern hemisphere. This renders it very difficult for patients and parents to completely avoid wheat, especially among those with high sensitivity to wheat. Reading food labels is mandatory. Caregivers for wheat allergic patients should be aware of wheat-containing foods in their individual localities. Several parents resort to cooking their own foods entirely for their infants. This usually brings hardship to parents and grandparents responsible for preparing foods for their infants. Several families in Eastern cultures use soy sauce to increase (salty) taste and palatability of their foods. Not commonly known to the public, wheat is an important component of most soy sauces (composing up to 20% in weight/volume). Elimination of soy sauce for daily cooking would preclude cooking of several essential meals such as baked fish and tasty fried rice. Moreover, some families avoid eating out altogether to ensure complete wheat avoidance. Quality of life among families with a wheat allergic child was shown to be more adversely affected compared to families with children allergic to other types of food (54). School entrance at 3-4 years of age is a critical time for parents of toddlers who do not become naturally tolerant to wheat. Food anaphylaxis can be a frightening experience for allergic children, their parents and school personnel. Management and prevention of food allergy in school is still under a developing phase even in developed nations such as in the US (55) and the European Union (56). Polloni et al, studied 440 school teachers and caretakers from school in northeast Italy, demonstrated a lower self-efficacy in recognizing symptoms of food allergy, administering drugs and guaranteeing full participation to extra-curricular activities to food-allergic students (57). Due to these facts, several parents with wheat allergic children often seek to have their children to undergo wheat OIT prior to school entrance. 5.2 Spontaneous remission (natural tolerance) of wheat allergy As with other food allergies, a large number of children with wheat allergy attained natural tolerance to wheat as age progresses. Keet et al, retrospectively evaluated 103 children with wheat allergy (with rate of anaphylaxis at 45%), found 29% developed natural tolerance by age 2 years which increased to 70% at 14 years of age (8). The median age of tolerance acquisition was 79 months (IQR 42-190 months). Peak wheat sIgE correlated with median age to attain tolerance, i.e, 145 months for those with highest level (>50 kU A /L) compared to 54 months for those with levels between 20 – 50 kU A /L and 31 months among those with level < 20 kU A /L). Of importance, 21% of those with wheat sIgE wheat indicating that natural tolerance could occur even at this very high level of wheat sIgE. A comparison of wheat sIgE between those with persistent wheat allergy and those with wheat allergy resolution was undertaken. Clearly, those with persistent wheat allergy had wheat sIgE levels higher than the wheat-tolerant group (8). Additionally, among the persistent group, wheat sIgE continued to rise during the first 2 – 3 years of observation and reached a plateau at around 4 – 6 years of age. This rise could possibly be due to accidental exposures, which increased the effect on wheat sensitization. A recent study from Japan by Koike et al also supported these findings (58). From Asia, two studies from Japan indicated that natural tolerance to wheat was noted in 66 – 75% of wheat allergic children by 6 years of age (58, 59). History of anaphylaxis, comorbid egg allergy, high level of sIgE to wheat and to ω-5 gliadin were risk factors for persistence of allergy to wheat. Similarly, Siripattanamongkol et al from Thailand reported a 69% rate of tolerance at the age of 9 years. In this study sIgE to ω-5 gliadin >0.35 kU A /L was the sole predictor for tolerance (60). 5.3 Consideration for wheat oral immunotherapy (WOIT) Obviously, many wheat allergic children undergo spontaneous remission. It is therefore prudent to allow an observation period for these young children allergic wheat. The age of six years has been commonly chosen as the age for WOIT. However, as evident from both the Keet (8) and the Koike (58) studies, a rise of wheat sIgE could occur during the first 2 years of life. Together with findings from studies on peanut OIT among younger infants (61, 62), there has been an increased tendency to start WOIT earlier, especially among those with substantial increases of wheat sIgE. However, food OIT in younger infants is still a controversial issue and is still subjected to ethical consideration, since young children deserve some input int the decision to undergo OIT, despite parental consent. As above, there is no absolute indication for wheat OIT. Experts in food allergy would consider WOIT in older children with both parental consent and patient assent for the procedure. No absolute level for wheat sIgE level has been recommended for OIT. However, it is advisable that WOIT be reserved for those with high sIgE to wheat of 20 kU A /L or greater, with age over 6 years, with rising wheat sIgE during the early observation period and with frequent accidental exposures with/without anaphylaxis. An important international consensus on Preparing Patients for Oral Immunotherapy (PPOINT) was published recently. This report used the Delphi methodology to arrive at several decision points among food allergy experts to consider various issues before initiating oral immunotherapy (63). Four different themes were agreed upon: 1. general considerations for counseling patients about OIT; 2. patient- and family-specific factors that should be addressed before initiating OIT and during OIT; 3. indications for initiating OIT; and 4. potential contraindications and precautions for OIT. Contraindications included both patient’s factors (such as presence of eosinophilic esophagitis and uncontrolled asthma) and parental factors (such as severe anxiety, presence of language barrier, obsessive-compulsive disorders, unwillingness to use epinephrine injections, poor adherence) should be considered. Other related issues such as alternative treatments to OIT, when to discontinue OIT, and how to mitigate accidental exposures were also discussed. The readers are encouraged to read this important compendium prior to and during OIT procedures, not only for OIT to wheat but also to other foods such as cow’s milk, eggs and peanuts. Other published guidelines on OFC and OIT are also available (64, 65). 5.4. Oral immunotherapy (OIT) for children with wheat allergy All children undergoing OIT should be subjected to oral food challenge, preferably via double-blind, placebo-controlled food challenge using a standardized protocol. The readers are referred to a recently revised EAACI and AAAAI PRACTALL protocol for OFC (48). Many children considered for WOIT would be classified as high-risk patient and should have an intravenous line in place for emergency IV access. Generally, the starting dose of wheat challenge should be 1 to 3 mg of wheat protein commonly administered as wheat powder (containing 10% wheat protein). Dose increment at log 3 increment is recommended at in a 20 – 30 minutes intervals. Challenges are terminated when obvious clinical signs or severe allergy symptoms occur. The dose causing reaction is defined as the ‘eliciting dose – ED’. One dose below ED is a starting dose for OIT with/without an escalating in-hospital day. The patient is then discharged with the tolerated dose to be taken daily. Up-dosing may be performed either at home (in patients with a history of only minor symptoms) or at a hospital visit (with high degree of severity) at 2 – 4 weeks interval. Targeted (threshold) doses of wheat varied among studies. Low threshold doses of 100 mg or less were studied among US and Japanese children with severe wheat allergies (9, 66-70). The rationale behind this approach is to initiate a change in immune response with smaller doses of wheat. Such a procedure resulted in some degree of wheat tolerance that allowed patients to consume small to moderate amounts of wheat without symptoms. On the other hand, some studies followed traditional target dosing regimens aiming for patients to tolerate conventional daily consumption of wheat (such as 1 piece of bread – containing up to 1.5 grams of wheat protein, a cup of noodles – 4.5 grams and pasta – up to 4.5 grams). This high vs low targeted (maintenance) dose determines the duration of dose escalation and perhaps affects the frequency of adverse reactions encountered during the OIT period. Rodriguez del Rio et al reported successful WOIT among 6 moderately severe wheat allergic children (71). Five of these 6 patients finished the dose escalation phase in 3 – 24 days and were able to tolerate 100 grams of pasta (12.56 grams) after 6 months of maintenance therapy. Mild adverse reactions were noted in 6% in the up-dosing period. Since this original trial, there have been 11 studies on WOIT among children 4 years of age and older (Table 1). There was one study from Finland (72), one multicenter trial from the US and the EU (9), and 9 studies from Asia, i.e, from Japan, Korea and Thailand (66-70, 73-76). Table 1 summarizes overviews of these 11 studies. WOIT methods varied across these studies, including differences in the severity of subjects, maintenance doses, and efficacy evaluation. Different wheat materials were used in different studies including vital wheat gluten flour (concentrated wheat) in the US and EU studies (9), pasta in Finland, (72) udon noodles in Japan, (66-70, 73) wheat flour in Thailand (74, 75) and boiled wheat noodles in Korea.(76). OIT requires daily ingestion over a prolonged period, and in many cases, minute doses were administered, especially during the initial OIT phase. It is desirable to select materials that are easy to obtain in each region and that would allow for the measurement of minute quantities. The use of finished products such as pasta, udon and noodles requires weighing and cutting especially in the home environment. This could lead to inaccurate dosing affecting the effect of OIT, subsequent up-dosing adjustments and evaluation of side effects. Table 1 showed details of these 11 trials. The number of patients with the exception of that in the Finnish study (n = 100) were small (72). Only 2 studies were randomized controlled trials (9, 66, 73). Most studies selected 5-6 years as the starting age for WOIT. The median age among the Finnish children (72) was older (median = 11 years of age). There are two methods for evaluating the efficacy of OIT, i.e. (1) desensitization, defined as the ability to ingest wheat while on daily consumption, and (2) sustained unresponsiveness (SU), defined as a negative OFC after a period of stopping the maintenance dose. As noted in Table 1, there is a wide variation in cumulative tolerated doses used to define “desensitization”. Similarly, there is no universal agreement on the length of time following OIT discontinuation that constitutes SU, varying from 2 weeks to 6 months, although many investigators consider a period of 6 – 8 weeks off therapy to define SU. Perhaps due to variations in subjects’ symptom severity and sensitivity, maintenance doses and duration of OIT differed between studies (Table 1). Desensitization was used to assess efficacy in 2 studies, which demonstrated success from 50 % in the multicenter study (9) to 82% in a real-life study from Korea (76). Two studies from Thailand reported a low rate of achieving the maintenance dose (23-39%) (74, 75). This could be due to a bias in selecting patients with high level of wheat sensitivities. Rates SU were much lower and ranged from 13%-69%. Based on these results, most children could achieve desensitization, but not many patients would be able to reach SU. Nowak et al randomized subjects to receive either low-dose OIT (a target dose of 1445 mg for two years) vs high-dose OIT (a target dose of 2748 mg for one year after crossing over from placebo). The desensitization rate two years in the low-dose OIT group (cumulative dose of 7743 mg) was 30% while that in the high-dose OIT group (one year treatment) was 57%, suggesting that high-dose OIT could provide a higher therapeutic benefit than a shorter period (9). Likewise, Ogura randomized subjects to receive high-dose OIT at a target dose of 2600 mg vs moderate-dose of 650 mg. After 1 year of therapy, proportion of participants achieving sustained unresponsiveness (SU) was 50.0% in the high-dose OIT group compared to 16.7% in the moderate-dose OIT group, again supporting the preferred higher dose treatment (73). In Japan, a new approach of low-dose OIT was designed for children with high sIgE levels and with more severe allergic symptoms. A three-year low-dose OIT program targeting 53 mg was administered to children with a history of wheat anaphylaxis and with reaction thresholds below 53 mg of wheat protein on wheat OFC. As shown in Figure 3, proportion of participants achieving SU (2-week intermission) to a dose of 400–660 mg increased annually as follows: 7% after one year, 28% after two years, and 41% after three years (68). Furthermore, in a six-year follow-up of the same patients, the 2-week SU to 400–660 mg continued to increase annually, and after six years 10% achieved a 2-week SU to a cumulative dose of 5200 mg.(69). Based on these results, low-dose wheat OIT could be an alternative treatment for those who may fail high dose wheat OIT. The stepwise OFC approach, beginning with a low dose would enable a more appropriate selection of candidates for OIT. Nevertheless, due to a long-term commitment to this low-dose approach, parental agreement, and adherence to the treatment program. Cost-effectiveness of this regimen remains to be further examined. In addition, low-dose OIT with only 53 mg/d (2 gm of Udon) was found to be associated with a reduction of allergic symptoms following accidental wheat ingestion with a reaction rate of 24% in the low-dose OIT group compared to 67% in the control group (p=0.01). Furthermore, the proportion of children who experienced anaphylaxis due to accidental ingestion was 14% in the low-dose OIT group and 50% in the control group (p=0.04) (68). These findings suggest that long-term low-dose OIT may prevent symptoms caused by accidental ingestion (77, 78). This could bring about a relief to the strenuous lifestyle of complete wheat avoidance in several families. Rates of adverse reactions from WOIT varied among studies due to patient selection, levels of wheat sIgE and to OIT protocols used. For instance, in a study by Wongteerayanee et al, 20% of severe wheat allergic patients required adrenaline administration (74). This could be due high level of wheat sIgE in this study (median of 198 kU A /L). In contrast, most adverse reactions among the Japanese children utilizing low-dose OIT was mild (67-69). It is quite clear that children with different wheat sensitivities need different WOIT approaches to minimize adverse reactions during OIT. It also accentuates the need for allergists experienced with OIT to supervise OIT in highly sensitive patients. Besides OIT, sublingual/swallow immunotherapy of 1 mg of gluten flour was tried in the treatment of 3 adult patients with WDEIA. All three patients showed increased thresholds (20, 80, and 120 g gluten with cofactors) during the three-year treatment period (79). Despite the recent FDA approval for the use of omalizumab for treatment of food allergy (80), wheat OIT preceded by eight weeks of omalizumab injections was reported in only one patient. A negative DBPCFC with 2 grams of wheat was observed after 36 weeks of omalizumab plus wheat OIT (81). It is noteworthy that after successful wheat OIT, wheat-dependent, exercise-induced anaphylaxis could still be observed (15, 82). Symptoms are similar to classic WDEIA, but generally less severe. This condition is not only limited to wheat OIT, but also has been described with egg and cow’s milk OIT (83). Consequently, this condition has been termed “exercise-induced allergic reaction on desensitization” (EIARD). Since 25% - 52% of wheat OIT children were reported to experience EIARD (83), it is prudent to advise patients not to undergo strenuous exercise after wheat consumption for 2 to 4 hours. Taken one step further, one may want to perform an exercise with wheat challenge after attaining the maintenance dose of wheat OIT to properly counsel families about the risk of participating in competitive sport. Summary and concluding remarks Immediate allergic reactions, particularly anaphylaxis from wheat has received increasing attention from allergists worldwide. Reasons for the increase in prevalence of wheat allergy in certain parts of the world is not entirely clear and requires further investigations. The study on hydrolyzed wheat allergy from Japan suggested that percutaneous absorption could be the route for sensitization to wheat in adults. Whether this is true in children and what would be sources of wheat allergens in the environment needs to be further studied. Such knowledge could lead to better understanding in pathophysiology of wheat allergy and proper prevention of wheat allergy in high-risk children. Wheat allergens are diverse and their responsible roles in initiating allergy symptoms and its severity are not clear. As a result, roles for diagnostic tests such as CRD, epitope-specific sIgE, BAT and MAT need to be further explored prior to use in general allergy practices. Oral imunotherapy either conventional or low-dose wheat OIT is efficacious in the therapy of immediate wheat allergy. 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Supplementary Material File (figures for combined manuscript 03-07-25.docx) Download 3.59 MB File (table 1a conventional oit table 1 - pv 220625 - nakagura 42025.docx) Download 52.35 KB File (table 1b -low-dose oit table 1 - pv 220625- nakagura 42025.docx) Download 47.31 KB Information & Authors Information Version history V1 Version 1 04 July 2025 Peer review timeline Published Pediatric Allergy and Immunology Version of Record 11 Feb 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Allergy and Immunology Authors Affiliations Pakit Vichyanond 0000-0001-5103-2916 [email protected] Mahidol University Faculty of Medicine Siriraj Hospital Department of Pediatrics View all articles by this author Ken-ichi Nagakura Sagamihara Chuo Byoin View all articles by this author Punchama Pacharn 0000-0002-2507-2057 Mahidol University Faculty of Medicine Siriraj Hospital Department of Pediatrics View all articles by this author Gary Wong 0000-0001-5939-812X The Chinese University of Hong Kong Department of Paediatrics View all articles by this author Hugh Sampson 0000-0003-1613-8875 Icahn School of Medicine at Mount Sinai Department of Pediatrics View all articles by this author Metrics & Citations Metrics Article Usage 602 views 317 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Pakit Vichyanond, Ken-ichi Nagakura, Punchama Pacharn, et al. WHEAT ALLERGY, A NEW AND EMERGING THREAT OF FOOD ALLERGY FOR CHILDREN. 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