Oral Wheat Immunotherapy in a Patient with Anaphylaxis Despite Negative Sensitization Tests


avatar Mahsa Rekabi 1 , avatar Saba Arshi 2 , avatar Sepideh Darougar ORCID 1 , * , avatar Vahab Rekabi 3 , avatar Mohammad Nabavi ORCID 2 , avatar Morteza Fallahpour 2 , avatar Mohammad Hassan Bemanian 2 , avatar Abolfazl Rajabi 4

Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
Department of Allergy, Hazrate Rasoul Hospital, Iran University of Medical Sciences, Tehran, Iran
Department of Molecular Pathology and Cytogenetics, Islamic Azad University of Medical Sciences, Tehran, Iran
Department of Radiology, Shahid Beheshti University of Medical Sciences, Tehran, Iran

how to cite: Rekabi M, Arshi S, Darougar S, Rekabi V, Nabavi M, et al. Oral Wheat Immunotherapy in a Patient with Anaphylaxis Despite Negative Sensitization Tests. Shiraz E-Med J.20(2):e83309. doi: 10.5812/semj.83309.



Wheat allergy can develop at any stage of life. The aim of this report was to demonstrate that skin testing and specific IgE have poor specificities and sensitivities for wheat allergy.

Case Presentation:

A 37-year-old female presented symptoms that were initiated immediately after consumption of bread and biscuits. She was well until two months prior to her recent admission. Her skin prick test, RIDA assay, and patch test for wheat showed negative results despite a history of two episodes of anaphylaxis. She underwent an oral food challenge, which confirmed wheat allergy. A desensitization procedure was recommended for her. At the end of the immunotherapy process, she had normal intake of wheat without any symptoms.


Negative sIgE and SPT results do not rule out clinical food allergy. Oral food challenges are still the cornerstone of diagnosis of food allergy.

1. Introduction

Food allergy is a general health problem in children and adults all over the world, affecting 5% of adults and if IgE-mediated, it is associated with a high risk of fatal anaphylaxis (1). Wheat is a widely consumed grain and it is estimated that almost a half of calories consumed by humans worldwide come from cereals , particularly wheat (2). Wheat has a high nutritional value and palatability (3). Gluten is a mixture of seed storage proteins found in wheat, which may trigger all kinds of gluten-related disorders (4). Gluten-related disorders, such as wheat allergy and celiac disease, are immune-mediated conditions, while non-celiac gluten sensitivity occurs as symptomatic adverse reactions, in which neither allergic nor autoimmune mechanisms are involved (5). Wheat allergy is known as an uncommon cause of food allergy in adults, particularly when addressing IgE-mediated mechanisms (6). However, wheat allergy can develop at any stage of life. Some people can eat bread for years without any ill effects and then suddenly one day develop symptoms of wheat allergy due to a gradual build-up of wheat antibodies over time, which, by reaching a critical level, could develop into respiratory, gastrointestinal and skin reactions.

The aim of this report was to demonstrate that although skin testing and specific IgE are routinely used to identify sensitization to food, they have poor specificities and sensitivities for wheat allergy. Therefore, oral food challenge still acts as the gold standard for identification of real wheat allergy.

2. Case Presentation

A 37-year-old female was presented to the researchers’ allergy clinic for symptoms that were apparently initiated immediately after consumption of bread and biscuits. She had an unremarkable medical history with normal developmental milestones during childhood. She was otherwise normal without any history of infantile gastrointestinal reflux or colitis, atopic dermatitis, allergic rhinitis, weight loss or chronic diarrhea during childhood, except for a state of drowsiness and a sense of itching, which occurred following consumption of bread and biscuits. However, these objective symptoms were overlooked and she did not seek medical attention at that time.

She was well until two months prior to her recent admission at the age of 37 when she experienced itching, flushing, hypotension, arthralgia, and dizziness after eating bread and biscuits. Surprisingly, these symptoms were more prominent during winter and they were severe enough to be initiated even by opening of the biscuit box, without eating a piece. There was no similar history in other family members and her siblings. Her first anaphylactic episode manifested with generalized body itching, headache, breathing difficulty, hypotension (70/55 mmHg), and vomiting 20 minutes after eating a biscuit. She recovered completely from this anaphylactic episode yet continued to have two more attacks following bread consumption before presenting to the allergy clinic.

The patient underwent a thorough screening for infectious, hepatic, and metabolic disorders. Table 1 illustrates the results of some of the assays performed for the patient.

Celiac disease was excluded due to normal serology (Table 1). Her skin prick test was negative, showing no sensitivity, particularly to wheat and grass. The RIDA assay and patch test for wheat were also negative. Her pulmonary function test was normal. Nasal smear revealed no eosinophilia. Furthermore, C1q, anti-C1q, anti-LKM, and immune profile, including serum complement levels, were all normal.

Table 1. Results of the Laboratory Tests
TestResultReference Value
WBC, cell/micL5.93P = 56, L = 35, Mo = 7, E = 2
Hg, g/dL14.3
FBS, mg/dL8870 - 110
BUN, mg/dL165 - 23
Creatinine, mg/dL0.80.6 - 1.2
Cholesterol, mg/dL268150 - 200
Triglyceride, mg/dL13230 - 200
AST, IU/L18Up to 40
ALT, IU/L16Up to 40
T3, ng/dL10560 - 220
T4, mcg/dL7.54.5 - 12.5
TSH, micIU/mL1.40.4 - 6.1
Prolactin, micIU/mL14930 - 819
Anti Endomysial Ab (IgG)Negative titerUp to 1/10
Anti Endomysial Ab (IgA)Negative titerUp to 1/10
Anti Gliadin Ab (IgA), U/mL35Up to 12
Anti Gliadin Ab (IgG), U/mL1.2Up to 12
Anti tissue transglutaminase, U/mL3 < 12
IgA (serum), mg/dL104.771 - 360
HBsAb, mIu/mL505 ≥ 10
Helicobacter (IgG), Au31.2 < 20
Helicobacter (IgA), Au38.9 < 20

Because of the existing discrepancy between history and test results, it was decided to perform an oral food challenge. The purpose of the challenge was simply to prove that the patient is allergic to wheat, despite her negative test results. The challenge was performed after taking a formal consent in a semi-intensive care unit with all necessary resuscitation equipment. The patient had an intravenous access established. Wheat and rice flour (as placebo) were prepared. The patient did not show any symptoms while receiving rice flour, yet during the administration of wheat, she developed erythematous skin rash (hives), hypotension, and abdominal pain. Therefore, the challenge was stopped and treatment for anaphylactic reaction was initiated. A desensitization procedure was recommended.

Oral immunotherapy was commenced with a starting dose of 0.01 mg of wheat protein, according to the OIT protocol shown in Table 2. During six months of desensitization, she had two episodes of anaphylaxis with signs and symptoms, including angioedema, flushing, hypotension, pruritic erythematous skin, arthralgia, and musculoskeletal complaints. At the end of the immunotherapy process, which lasted six months, she had normal intake of wheat without any symptoms. Then, a second challenge procedure was performed with all kinds of flour available in the market to assess tolerance induction. At this point, the patient tolerated all types of bread without any signs and symptoms.

Table 2. Oral Desensitization Protocol Used for the Patient
DayDilution1st Dose/DayLast DoseFinal DoseSolution, mg/cc
First Phase: 0.02 g/mL (Semolina)
1 - 180.01 mg/cc1 mL10 mL0.3 mg10/1000
19 - 300.1 mg/cc3 mL10 mL3 mg100/1000
31 - 391 mg/cc3 mL10 mL30 mg1000/1000
40 - 482 mg/cc6 mL10 mL60 mg2000/1000
49 - 574 mg/cc15 mL10 mL120 mg4000/1000
58 - 1204.5 mg/cc25 mL75 mL1000 mg4500/1000
DayFirst DoseLast DoseFinal Dose
Second Phase: 1 - 1.4, g (Pasta)
121 - 1442 pastas15 pastas twice a day42 g
145 - 20015 pastas twice a day100 pastas a day70 g

3. Discussion

Wheat allergy is more common in children and according to the American College of Asthma, Allergy and Immunology, about 65% of children outgrow the allergy by the time they reach adolescence. The prevalence of wheat allergy is about 0.5%, worldwide (7). While the symptoms of wheat allergy are usually mild, in some cases it may become severe, although wheat has never been reported as the cause of fatal anaphylaxis (8). According to a study performed by Scibilia et al. wheat is an important food allergen in adults and should not be overlooked in this age group (6).

The diagnosis of wheat allergy is based on patient’s clinical history, detection of wheat-specific IgE, and on the results of food elimination diets and oral challenges (8). Once the patient is suspected to suffer from wheat allergy, the diagnosis should be confirmed by demonstration of wheat specific-IgE.

The clinical case presented in the current report showed negative skin prick test and RIDA, despite two episodes of anaphylactic reactions following ingestion of wheat. According to the literature, it is believed that wheat extract IgE testing has a low specificity (2) with a poor predicting value (1). Again, freshly made solution with wheat flour, which was prepared and used for skin test did not contain insoluble major wheat allergens, such as prolamins. In recent studies, component resolved diagnosis (CRD) has gained interest (1). Considering the role of major wheat allergens, which are relevant for inducing food allergy in Japanese and Swedish studies, Tri a 19, correlated better with OFC-proven IgE-mediated wheat allergy. However, this test was not approved by other studies. This test is not available in Iran. Less difficult blood tests, including Basophil Activation test are also not available in Iran. Since oral food challenge is a far more accurate test, it was performed to confirm a true allergic event. Furthermore, the efficient wheat oral immunotherapy protocol used for this patient with a history of multiple episodes of anaphylaxis following consumption of wheat products, demonstrates real food allergy, despite negative in vitro and in vivo tests.

3.1. Conclusion

This case confirms the difficulty in diagnosis of wheat allergy. Negative sIgE and SPT results do not rule out clinical food allergy. Also, the size of the skin prick test and the levels of specific IgE are not useful neither in diagnosis of wheat allergy nor in evaluation of wheat tolerance. Despite the risk of severe allergic reactions with oral food challenges, they are still the cornerstone of diagnosis of food allergy and other tests should be considered as additional tools to aid in the diagnosis of food allergy.


  • 1.

    Santos AF, Brough HA. Making the most of in vitro tests to diagnose food allergy. J Allergy Clin Immunol Pract. 2017;5(2):237-48. doi: 10.1016/j.jaip.2016.12.003. [PubMed: 28283150]. [PubMed Central: PMC5345384].

  • 2.

    Czaja-Bulsa G, Bulsa M. What do we know now about IgE-mediated wheat allergy in children? Nutrients. 2017;9(1). doi: 10.3390/nu9010035. [PubMed: 28054973]. [PubMed Central: PMC5295079].

  • 3.

    Cianferoni A. Wheat allergy: Diagnosis and management. J Asthma Allergy. 2016;9:13-25. doi: 10.2147/JAA.S81550. [PubMed: 26889090]. [PubMed Central: PMC4743586].

  • 4.

    Balakireva AV, Zamyatnin AA. Properties of gluten intolerance: Gluten structure, evolution, pathogenicity and detoxification capabilities. Nutrients. 2016;8(10). doi: 10.3390/nu8100644. [PubMed: 27763541]. [PubMed Central: PMC5084031].

  • 5.

    Ontiveros N, Lopez-Gallardo JA, Vergara-Jimenez MJ, Cabrera-Chavez F. Self-reported prevalence of symptomatic adverse reactions to gluten and adherence to gluten-free diet in an adult mexican population. Nutrients. 2015;7(7):6000-15. doi: 10.3390/nu7075267. [PubMed: 26197336]. [PubMed Central: PMC4517044].

  • 6.

    Scibilia J, Pastorello EA, Zisa G, Ottolenghi A, Bindslev-Jensen C, Pravettoni V, et al. Wheat allergy: A double-blind, placebo-controlled study in adults. J Allergy Clin Immunol. 2006;117(2):433-9. doi: 10.1016/j.jaci.2005.10.014. [PubMed: 16461145].

  • 7.

    Nam YH, Hwang EK, Jin HJ, Lee JM, Shin YS, Ye YM, et al. Comparison of specific IgE antibodies to wheat component allergens in two phenotypes of wheat allergy. J Korean Med Sci. 2013;28(11):1697-9. doi: 10.3346/jkms.2013.28.11.1697. [PubMed: 24265539]. [PubMed Central: PMC3835518].

  • 8.

    Mohamed Z, Sathiya M. A case of wheat-dependent exercise-induced anaphylaxis. Indian J Allergy Asthma Immunol. 2014;28(1):52. doi: 10.4103/0972-6691.134227.

Copyright © 2018, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.