Summary

Wheat (Triticum aestivum) is the third most important crop across the globe and grows in various climatic conditions. Wheat grain is high in nutritional content and is processed into several food items. Allergic reactions to wheat are mainly attributed to its protein content. The wheat proteins are classified as glutens (gliadins and glutenins) and non-glutens (α-amylase inhibitors, lipid transfer proteins and avenin-like proteins). The prevalence of wheat allergy (WA) differs across geographies and among different age groups. It is considered as the third most common allergy, after cow’s milk and egg in countries such as, Japan, Korea, Finland, Germany, and the United States. Wheat can induce both immunoglobulin (Ig) E-mediated as well as non-IgE-mediated food allergies. The IgE-mediated allergies include food allergy manifested as angioedema, nausea, abdominal pain, anaphylaxis including wheat dependent exercise-induced anaphylaxis (WDEIA), respiratory allergy (Baker’s asthma) as well as skin allergy (contact urticaria). The non-IgE-mediated ones include enterocolitis syndrome, eosinophilic esophagitis and non-celiac gluten sensitivity. Wheat allergy can be induced by oral ingestion, or by inhalation of wheat flour as well as through skin contact. There are several allergens (~28) identified from wheat, of which major allergens are found from the gluten family, in addition to some of the non-gluten proteins. Sensitization to Tri a 17, 19, 20, 26, and 37 in IgE-mediated wheat-allergic patients may indicate the presence of severe allergic reactions, while especially Tri a 19 have been reported as markers for WDEIA. Further, Tri a 27 and Tri a 28 have been found to be the most important wheat allergens in patients with Baker’s asthma. It is recommended that individuals allergic to wheat should strictly avoid the consumption of wheat and its products. Further, cross-reactivity has been shown between cereals of the same family i.e. between wheat, barley and rye. Being sensitized to wheat is common, mainly due to cross-reactivity to grass. Up to 60% of grass-allergic subjects are sensitized to wheat but can tolerate it. A positive wheat test always needs to be further investigated in order to know if the test results are clinically relevant or due to pollen cross-reactivity.

Epidemiology

Worldwide distribution

Wheat allergy (WA) occurs in many ways (food allergy in children, WDEIA, Baker’s asthma or skin allergy) and its prevalence differs across the geographies and among different age groups. It is considered as the third most common allergy, after cow’s milk and egg in countries such as, Japan, Korea, Finland, Germany, and the United States (US) (in preschool children).

The prevalence of WA among 1612 children with food allergies was found to be 1% in a study conducted in US. Further, the prevalence of IgE-mediated WA in young children (age: <14 years) was analyzed in 4 studies involved in a systematic review conducted on 36 studies. It was found to be between 0.2% and 0.5%, based on an oral food challenge (OFC) conducted among young children in Denmark, Germany and the United Kingdom (UK). Another systematic review involving 25 WA studies in Europe reported an estimated pooled prevalence of 0.3% across all age groups, based on OFC or history of WA. Additionally, in a study conducted in Finland among 108 children (age: 0.6-17.3 years) with suspected WA, who underwent OFC, 52.8% of children reacted positively (30 with immediate symptoms and 27 with delayed symptoms). Also, in a birth cohort study involving 827 children in UK, WA was confirmed in 0.48% of children, based on OFC.

A systematic review of 66 studies reported the prevalence of WA in Asia-Pacific region (Iran, Japan, Korea, Malaysia, Singapore, Pakistan, Australia). According to the results, the prevalence was reported between 0.16% and 0.37% via studies conducted in general population and between 10.4% and 26.1% via studies conducted among allergic population. Further, a retrospective study conducted in Korea among 1353 children and adolescents (0-18 years) with immediate reactions to food reported 1661 cases of food-allergic reactions in a span of one year. Wheat was reported to be the cause of immediate food-allergic reactions in 7.9% cases. Additionally, a prevalence study conducted in India among 4680 allergic patients (all age groups) with sensitization to different foods, WA was reported in 21.8%.

Severe reactions in wheat-allergic patients could also lead to anaphylaxis (wheat induced anaphylaxis [WIA]). A study analyzed the risk of near-fatal anaphylaxis due to wheat in 93 US children who underwent OFC after consuming low doses of wheat. It was found that wheat could be an independent risk factor for anaphylaxis, which was reported to be in 42% of patients. Interestingly, WDEIA is one of the most severe forms of WA in adults and various studies have shown w-5-gliadin sensitization in most of the WDEIA patients. A study conducted on 167 cases of food-dependent exercise-induced anaphylaxis in Japanese patients found that the causative agent in >50% of the cases was wheat. Further, a recent prospective study conducted among 33 Thai-allergic patients found WDEIA to be more prevalent than WA (WDEIA: 69.7% vs. WA: 30.3%).

It has also been shown that skin sensitization due to exposure to wheat proteins could lead to WA. This was observed in 2111 Japanese adults (age:1-93 years) in a survey (April 2012 to October 2014), who were sensitized to wheat due to the use of special facial soap containing hydrolyzed wheat proteins. These adults, who were previously non-allergic to wheat, developed allergic reactions due to wheat consumption after such cutaneous sensitization.

Wheat allergy is also manifested as IgE-mediated respiratory allergy, clinically presented as occupational asthma (Baker’s asthma) and rhinitis. The prevalence of occupational asthma and/or rhinitis due to wheat hypersensitivity was found to be 25.1% in Spain during a study conducted among workers from cereal industries.

Risk factors

Genetic predisposition is one of the risk factors for the development of food allergies, including WA in patients. Further, sensitization to egg, cow’s milk, and grasses are also reported to be associated with the risk for WA.

Alcohol and intake of non-steroidal anti-inflammatory drugs (NSAIDs) may be considered as cofactors for WDEIA reactions, that may precipitate it, even in the absence of exercise.

Pediatric issues

The IgE-mediated WA is common in children. The prevalence of this allergy is reported to be higher in children as compared to adults in general. Furthermore, it is also documented that the majority of children outgrow their allergies by the time they reach 12-14 years. With respect to the clinical manifestations of IgE-mediated food allergies, the gastrointestinal (GI) symptoms have been frequently observed in young children, which reduces with age, as compared to the skin symptoms. On the contrary, severe systemic reactions, like anaphylaxis is more noted in adults or teens than in children.

Route Of Exposure

Main

Oral ingestion of wheat is the major route of exposure leading to IgE-mediated food-allergic reactions within 2 hours of its intake. In addition to this, WDEIA has also been reported to be precipitated as a result of physical exercise, following oral ingestion of wheat-based products.

Furthermore, inhalation or handling of wheat flour could lead to Baker’s asthma or rhinitis in sensitized individuals.

Another important route of exposure to WA includes skin contact with hydrolyzed wheat proteins, which could manifest as contact urticaria.

Clinical Relevance

Wheat can induce both IgE-mediated as well as non-IgE-mediated food allergies. The IgE-mediated allergies include food allergy, such as skin allergy (angioedema, contact urticaria), nausea, abdominal pain, bronchial obstruction, anaphylaxis, as well as WDEIA. The non-IgE-mediated ones include enterocolitis syndrome, eosinophilic esophagitis and NCGS.

Food Allergy and Anaphylaxis

Wheat allergy occurs predominantly in children with a familial predisposition of atopy. It is usually IgE mediated and the clinical manifestation occurs within 1-2 hours of its intake.

In a US-based study, 39 out of 93 children undergoing oral wheat challenge were found positive. The allergic reactions observed during oral wheat challenge were classified as cutaneous (urticaria, angioedema, erythema, or AD), respiratory (wheezing, dyspnea, tachypnea, cough, sneezing, rhinitis, or throat tightness), GI (diarrhea, vomiting, or abdominal pain), cardiovascular (hypotension), neurological (syncope) and multi-organ system. Further, the OFC with wheat resulted in multi-organ systemic reactions in 28 children.

In a prospective analysis performed on 50 children with WA, 88% reported GI symptoms (62% with vomiting, 44% with diarrhea and 8% with abdominal pain). The other symptoms observed were cutaneous reactions (urticaria, erythema) in the range of 40-50%, bronchospasm in around 10% and anaphylaxis in the range of 10-15%. It was found that 32% of children developed WA, when they were in infant stage. Interestingly, it was observed that WA in these children resolved with age and by the age of 18 years, 76% children had outgrown their allergy. The 12 children with persistent WA showed more prominent anaphylaxis (about 50%) and bronchospasm (40-45%) as compared to skin or GI reactions.

A retrospective study conducted on 156 patients with a history of WA found 95 individuals to be having a history of food allergy due to wheat ingestion. The WA was confirmed in 21 individuals by food challenge test. Furthermore, the most commonly observed symptom in these 21 patients was urticaria (95.2%), along with other symptoms like pruritis, angioedema, erythema, diarrhea, vomiting, rhinitis and conjunctivitis.

In a study conducted in Finland among 108 wheat-allergic children (age: 0.6-17.3 years) subjected to OFC with wheat, a positive reaction was observed in 57 children (immediate reactions in 30 and delayed in 27), while 51 children responded negative to OFC. The most frequent symptoms observed were cutaneous (urticaria or erythema; 44%), followed by GI (26%), and respiratory symptoms (16%).

Furthermore, in a cross-sectional survey conducted among 100 children with WA (IgE-mediated), 49% of children presented with only skin reactions, while 51% of children presented with anaphylaxis due to wheat.

Wheat-dependent exercise-induced anaphylaxis (WDEIA)

The WDEIA is an occasional, but potential severe allergy caused due to wheat consumption combined with accompanying factors, such as physical exercise, aspirin, alcohol etc. It usually affects adolescents and young adults. This severe allergy can be evoked by physical exercise within 1 to 4 hours after wheat consumption. The occurrence of this severe reaction is rare, however, it has reportedly been more found in countries, such as Europe and Japan. It is generally manifested as pruritis, urticaria, angioedema as well as severe allergic reactions, such as intense sweating, abdominal colic, bronchial obstruction, syncope, and even systemic reactions, like anaphylaxis.

In a retrospective study conducted on 156 patients with a history of WA, 48 individuals were found to be having a history of allergy, due to wheat ingestion accompanied by exercise. However, on confirmation with exercise challenge on tread mill in addition to OFC, 10 individuals were found to have WDEIA. Furthermore, among the 10 confirmed WDEIA patients, all the patients were reported to have urticaria, with angioedema found only in one of them.

Further, it was reported that the wheat allergens found responsible for WDEIA were w-5-gliadin and HMW-glutenins. Besides these, other allergens which may also lead to WDEIA were α/β/g-gliadins along with LMW-glutenins.

A multicentric, retrospective study conducted on 132 adults with w-5-gliadin allergy (also known as WDEIA, severe anaphylaxis after wheat ingestion) in UK found wheat to be the causative agent in 82% of patients. Additionally, WDEIA was induced in 80% of patients due to exercise, while 25%, 9% and 5% were found due to alcohol, NSAIDs and heat, respectively.

Respiratory and skin allergy

Bakers asthma or rhinitis have been considered as the most common occupational diseases, occurring due to inhalation of wheat allergens among bakers or individuals working in mills/chocolate factories. Further, contact urticaria due to skin contact with wheat flour is the most common skin reaction, mostly noted in bakers as well as individuals working in mills/flour factories.

In a retrospective study conducted among 156 patients with a history of WA, 13 individuals reported to have the allergy due to wheat flour inhalation. However, on confirmation with nasal food challenge, 11 individuals (mostly bakers) were found to present with inhalational allergy to wheat. Furthermore it was reported that all the 11 patients presented with rhinitis, while conjunctivitis and asthma was reported in 54.5% and 18.2% of patients, respectively.

A study was conducted on 2111 Japanese patients with WA due to cutaneous sensitization via hydrolyzed wheat-proteins in a facial soap. It was found that most of the individuals presented with skin symptoms (urticaria, skin redness and itching; 71%) and eyelid swelling (40%) while using the soap. However, this sensitization resulted in food allergy which was observed as allergic reactions after wheat consumption. The allergic symptoms recorded after wheat ingestion from 899 patients were eyelid swelling (77%), urticaria (60%), dyspnea (43%), anaphylactic shock (25%), rhinitis (13%) and vomiting (11%).

Non-IgE-mediated immune disorders

The non-IgE-mediated immune disorders (eosinophilic GI disease and esophagitis) occurring due to wheat sensitivity has been observed in a prospective study conducted on 50 wheat-allergic children. According to the results, the eosinophilic GI disease and eosinophilic esophagitis was reported to be 12% (6 of 50) and 10% (5 of 50) of patients, respectively.

Atopic disorders (Allergic rhinitis, asthma and atopic dermatitis)

In a prospective analysis performed on 50 children with WA, atopic disorders, such as AR, AD and asthma was reported in 64%, 78% and 48% of patients, respectively.

In another study conducted in Finland among 108 suspected wheat-allergic children, 57 (30 with immediate symptoms and 27 with delayed symptoms) were found positive on oral wheat challenge. Atopic dermatitis, AR and asthma was observed in 84.2%, 35.1% and 19.2 of OFC-positive children, respectively.

Further, in a cross-sectional survey conducted among 100 children with WA, 47% of children presented with AD, 44% with AR and 14% with asthma.

Other diseases

Non-celiac gluten sensitivity (NCGS)

The NCGS or gluten sensitivity mainly occurs due to the consumption of gluten protein. This sensitivity is presented with GI reactions as well as extra-intestinal symptoms after consumption of gluten-containing foods, in patients who are not the candidates of celiac disease or WA disease. It is generally difficult to differentiate NCGS from celiac diseases or WA, owing to similar clinical manifestations, similar triggers as well as similar avoidance strategy.

The pathomechanism predicted for NCGS is attributed to the intolerance of wheat carbohydrates rather than wheat proteins. The wheat fructans or α-trypsin inhibitors may be considered as culprits for the same.

Prevention And Therapy

Prevention strategies

Avoidance

Individuals allergic to wheat should strictly avoid consumption of wheat and its products. Besides, occupational/domestic exposure to wheat allergens, in the form of wheat flour or dust should also be avoided. Furthermore, patients with WDEIA should be careful while performing strenuous physical activity, either alone, or during hot/humid condition or during pollination period.

Cross-Reactivity

Individuals allergic to wheat are often found to have cross-reactive allergy to other cereals as well, including barley and rye, and rarely to oats. This cross-reactivity may be taxonomically related as wheat, barley, rye, and oats belongs to the same family. The possible cross-reactivity among wheat, barley and rye may be attributed to the presence of homologous prolamin proteins, such as g-70 and g-35 secalins in rye, g-3 hordein in barley and w-5 gliadin in wheat. This cross-reactivity was shown in a study conducted on 23 patients with WDEIA, who had IgE sensitization as well as positive SPT to w-5 gliadin (wheat protein). The g-70 secalins (rye) was found IgE-reactive in 91%, g-35 secalin (rye) in 83% and g-3 hordein (barley) in 91% of sera of adult patients. Further, the cross-reactivity was also shown by positive SPT in 15 w-5 gliadin-positive WDEIA patients. The positive reactions observed with g-35 secalins, g-70 secalins, and g-3 hordein was 20%, 67% and 47% respectively. Additionally, proteins such as α-purothionins from these 3 cereals have found to exhibit >80% of sequence identity.

Clinical cross-reactivity among wheat and barley is also shown in a study conducted on 20 barley-allergic patients in Korea. Clinical WA was found in 75% of barley-allergic patients along with significant correlation (p<0.001) between IgE levels of wheat and barley. Besides, in a study conducted on 10 wheat-allergic individuals, cross-reactivity of wheat with barley, oats and Job’s tears was evaluated. The results reported a cross-reactivity rate of 60%, 33.3% and 20% with barley, oats and Job’s tears, respectively based on the clinical reactivity or SPT. Owing to this cross-reactivity, barley and rye along with wheat are proposed to be avoided in the 6-food elimination diet (avoiding all gluten containing grains) in patients with gluten sensitivity.

In a study conducted among patients with food allergy (including wheat), high levels of IgE antibodies, particularly to rice was displayed in these patients. In addition to this, maize LTP was found to possess 59-79% of sequence identity with wheat LTP. However, both rice and corn have been often looked upon as an alternative for the wheat-allergic patients. A study conducted on 18 wheat-allergic children showed negative outcomes when challenged with rice and corn.

Patients with grass pollen allergy may have wheat sensitization too, although this has been shown not to be of clinical relevance. This was reported by a study that was conducted on 63 children with doctor-diagnosed WA, sensitized to wheat and avoiding wheat in diet. Only 32 children were confirmed wheat-allergic based on OFC. Sensitization to grass was found in 73% of these children with significantly more sensitization in wheat allergic (n=32) as compared to non-allergic children (n=31). It was obvious from this study that many subjects were diagnosed by physicians to have WA but was shown not to react to wheat upon challenge. Thus, it was reported that cross-reactivity among grass pollens and wheat could give rise to false-positive sensitization results. Similarly, in another study conducted among a birth cohort of 827 children in UK, high levels of cross-sensitization was found between grass and wheat, however were clinically irrelevant.

Further, in another study conducted on 72 grass pollen-allergic patients who were able to consume wheat, 60% showed IgE sensitivity to wheat. Further, specific IgE towards wheat-specific allergen components (Tri a 14 and Tri a 19) as well timothy grass-pollen allergens (Phl p 1, 2, 4, 5, 6, 7, 11 and 12) were evaluated. It was shown that sensitization to Phl p 12 was found to be significantly (p<0.05) more in patients sensitized to wheat. However, all the children were able to consume wheat without any significant allergic reactions. Physicians should handle with care a positive IgE test to wheat in a grass-allergic patient. If the patient is consuming wheat without problem, the test result is most likely due to cross reaction between wheat and grass. If high levels to the wheat test are found, a possible WA should be further investigated.

Cross-reactivity between wheat and kiwi fruit in patients with Baker’s asthma has been noted which may be due to thiol proteases from wheat and carhohydrate determinants from kiwi.