Wheat allergy Presented by Athit Wutthisanwatthana, MD. January 18, 2019

1. Wheat Allergy
A Wutthisanwatthana

2. Grain Taxonomy
Kingdom: Plantae
Subkingdom: Embryophyta

3. Hemery Y, Rouau X, Lullien-Pellerin V, Cécile Barron C, Abecassis J. Dry processes to develop wheat fractions and products with enhanced nutritional quality. J Cereal
Sci. 2007 November;46(3)327-47

4. Wheat Protein (Triticum aestivum, Tri a)
• Proteomic analysis reveal >1,000 individual components
1. Water-soluble/salt-soluble: Albumin and globulins 15-20%
• Bata-amylase
• Inhibitors of hydrolytic enzyme – alpha-amylase, proteinases
• Non-specific lipid transfer proteins
• Purodoindolines
Tatham AS, Shewry PR. Allergens in wheat and related cereals. Clin Ex Allergy. 2008;38:1712-26
Cianferoni A. Wheat allergy: diagnosis and management. J Asthma Allergy. 2016 Jan 29;9:13-25

5. Wheat Protein (Triticum aestivum, Tri a)
2. Water-insoluble 80%
• Gliadins
• Alpha/beta-gliadin
• Gamma-gliadins
• Omega-gliadins – omega-5-gliadin (Tri a 19)
• Glutenins
• High molecular weight
• Low molecular weight
Tatham AS, Shewry PR. Allergens in wheat and related cereals. Clin Ex Allergy. 2008;38:1712-26
Cianferoni A. Wheat allergy: diagnosis and management. J Asthma Allergy. 2016 Jan 29;9:13-25

6. Major Allergens in Wheat Flour
Cianferoni A. Wheat allergy: diagnosis and management. J Asthma Allergy. 2016 Jan 29;9:13-25

7. Allergenic Similarities Between Cereal Grains
Palosuo K, Alenius H, Varjonen E, Kalkkinen N, Reunala T. Rye gamma-70 and gamma-35 secalins and barley gamma-3 hordein cross-react with omega-5 gliadin, a
major allergen in wheat-dependent, exercise-induced anaphylaxis. Clin Exp Allergy. 2001 Mar;31(3):466-73
Tanner GJ, Colgrave ML, Howitt CA. Gluten, Celiac Disease, and Gluten Intolerance and the Impact of Gluten Minimization Treatments with Prolylendopeptidase on
the Measurement of Gluten in Beer. J Am Soc Brew Them. 2014;72

8. Allergenic Similarities Between Cereal Grains:
Tri a 36
• 369-aa protein, low molecular weight glutenin
• Cross reactivity
• Rye
• Barley
• Oat
• Spelt
• Rice
Baar A, Pahr S, Constatin C, Scheiblhofer S, Thalhamer J, Giavi S, et al. Molecular and immunological characterization of Tri a 36, a low molecular weight glutenin, as a
novel major wheat food allergen. J Immunol. 2012 Sep 15;189(6):3018-25

9. The Frequency of Cross-Reactions within the Same Food Family
Ho MH, Wong WH, Chang C. Clinical spectrum of food allergies: a comprehensive review. Clin Rev Allergy Immunol. 2014 Jun;46(3):225-40

10. Allergenic Similarities to Grasses
• Homologous proteins with grass pollen
• High rate of sensitization
• Low rate of clinical reactivity
Weichel M, Vergoossen NJ, Bonomi S, Scibilia J, Ortolani C, Ballmer-Weber BK, et al. Screening the allergenic repertoires of wheat and maize with sera from double-
blind, placebo-controlled food challenge positive patients. Allergy. 2006 Jan;61(1)128-35

11. Epidemiology

12. IgE-Mediated Wheat Allergy
• Children
• Europe 0.2-1.3%
• US 0.4%
• University-based 18%
• Atopic dermatitis 13%
Venter C, Pereira B, Grundy J, Clayton B, Roberts G, Higgins Bernie, et al. Incidence of parentally reported and clinically diagnosed food hypersensitivity in the first year
of life. J Allergy Clin Immunol. 2006 May;117(5)1118-24
Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic Jacqueline. The prevalence, severity, and distribution of childhood food allergy in the United States.
Pediatrics. 2011 July;128(1)
Janine KM, Sichere SH, Sampson HA, Nowak-Wegrzyn A. Use of multiple doses of epinephrine in food-induced anaphylaxis in children. J Allergy Clin Immunol. 2008
Jul;122(1):133-8
Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics. 1998
Mar;101(3):E8
• Milk
• Peanut
• Tree nuts
• Wheat

13. Nowak-Wegrzyn A, Burks AW, Sampson HA. Reactions to foods. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s
allergy principles and practice. Philadelphia; Elsevier Saunders; 2014. 1095-105

14. Japan
Hen's egg
45%
Cow's milk
19%
Wheat
9%
Shellfish
7%
Fruit
7%
Buck wheat
5%
Fish
5%
Peanut
3%
PERCENT
• Doctors reported
• Year 2001-2002
• 3882 cases
Imai T, Ebisawa M. Nationwide Survey of Immediate Type Food Allergy in Japan. J Allergy Clin Immunol. 2004 February

15. Clinical Features

16. The spectrum of Food Allergy of Different Immunopathophysiology
Ho MH, Wong WH, Chang C. Clinical spectrum of food allergies: a comprehensive review. Clin Rev Allergy Immunol. 2014 Jun;46(3):225-40

17. Clinical Features
• IgE-mediated reaction
• Mixed IgE-mediated and non-IgE-mediated reactions
• Atopic dermatitis
• Allergic eosinophilic gastrointestinal disorders
• Non-IgE-mediated reaction
• Food protein-induced enterocolitis syndrome
• Protein-induced proctitis/proctocolitis
• Food protein-induced enteropathy
• Celiac disease

18. IgE-Mediated Reactions
• Immediate reaction
• More common in children than adults
• Presentation
• Skin – pruritus, flushing, urticaria, angioedema
• Oropharyngeal - pruritis
• Upper and lower respiratory tract - edema, hoarseness, stridor, dyspnea,
wheese
• Gastrointestinal tract – nausea, vomiting, diarrhea
• Cardiovascular – hypotension, tachycardia

19. Ho MH, Wong WH, Chang C. Clinical spectrum of food allergies: a comprehensive review. Clin Rev Allergy Immunol. 2014 Jun;46(3):225-40
A schematic diagram illustrating the time sequence and key factors precipitating the early- and late-phase reactions of food
allergy or anaphylaxis

20. Allergic Contact Urticaria
• Causative foods: Rice, wheat, fruits, vegetable, fish, shrimp, cuttlefish
• May precede food allergy
• Oral symptoms 93.3%
• Urticaria 26.7%
• Abdominal symptoms 20%
• Latency 1 month to 19 years (mean 8.7 years)
Inmate N, Nagashima M, Hakuta A, Aihara M. Food allergy preceded by contact urticaria due to the same food: involvement of epicutaneous sensitization in food
allergy. Allergol Int. 2015 Jan;64(1):73-8

21. Baker’s Asthma
• One of the most common forms of occupational asthma
• Rhinitis, asthma, conjunctivitis
• Atopic by skin or IgE test
• Latency period – months, years, decades
• Temporal relation between symptoms and period of bakery work
Brisman J. Baker’s Asthma. Occup Environ Med. 2002;59:498-502

22. Brisman J. Baker’s Asthma. Occup Environ Med. 2002;59:498-502

23. Food-Dependent Exercise-Induced Anaphylaxis
• Time between meal and exercise 30-120 min
• Causative foods: Shellfish, wheat products, vegetables, fruits, nuts,
eggs, mushrooms, corn, pork, beef, rice, cow milk
Wong GK, Krishna MT, Food-dependent exercise-induced anaphylaxis: is wheat unique? Curr Allergy Asthma Rep. 2013 Dec;13(6):639-44
Morita E, Matsuo H, Chinuki Y, Takahashi H, Dahlström J, Tanaka A. Food-dependent exercise-induced anaphylaxis -importance of omega-5 gliadin and HMW-glutenin
as causative antigens for wheat-dependent exercise-induced anaphylaxis. Allergol Int. 2009 Dec;58(4):493-8

24. Schematic Figures of Food Allergen Absorption in Gastrointestinal Tract in the Patients with FDEIA
Increased gastrointestinal permeability
Undigest immunoreactive allergen
Morita E, Matsuo H, Chinuki Y, Takahashi H, Dahlström J, Tanaka A. Food-dependent exercise-induced anaphylaxis -importance of omega-5 gliadin and HMW-glutenin
as causative antigens for wheat-dependent exercise-induced anaphylaxis. Allergol Int. 2009 Dec;58(4):493-8

25. Atopic Dermatitis
Zhu TH, Zhu TR, Tran KA, Sivamani RK, Shi VY. Epithelial Barrier Dysfunctions in Atopic Dermatitis: A Skin-Gut-Lung Model Linking Microbiome Alteration and Immune
Dysregulation. Br J Dermatol. 2018 Sep;179(3):570-81

26. Zhu TH, Zhu TR, Tran KA, Sivamani RK, Shi VY. Epithelial Barrier Dysfunctions in Atopic Dermatitis: A Skin-Gut-Lung Model Linking Microbiome Alteration and Immune
Dysregulation. Br J Dermatol. 2018 Sep;179(3):570-81

27. Food-Exacerbated AD Reactions
• Milk, eggs, pea- nuts, tree nuts, wheat, soy, fish and shellfish
• Flare: Increased erythema and pruritus of eczematous lesions
• Rare in adult

28. • Milk, egg, peanut 69%
• 14.8% has food hypersensitivity

29. Allergic Eosinophilic Gastrointestinal Disorders
The Spectrum of Gastrointestinal Inflammatory Disorders Involving Eosinophils
Rothenberg MC. Eosinophilic gastrointestinal disorders. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s allergy
principles and practice. Philadelphia; Elsevier Saunders; 2014. 1095-105

30. Rothenberg MC. Eosinophilic gastrointestinal disorders. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s allergy
principles and practice. Philadelphia; Elsevier Saunders; 2014. 1095-105

31. Jawairia M, Shahzad G, Mustacchia P. Eosinophilic Gastrointestinal Diseases: Review and Update. ISRN Gastroenterol. 2012
Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). J Allergy Clin Immunol. 2004 January

32. Food Protein-Induced Enterocolitis Syndrome
• Onset
• Frequently in the first months of life
• Can manifest at any age (reported 4-27 days1)
• After one year of age is rare
1Powell GK. Milk- and soy-induced enterocolitis of infancy. Clinical features and standardization of challenge. J Pediatr. 1978 Oct;93(4):553-60

33. Food Protein-Induced Enterocolitis Syndrome
• Acute
• Initial presentation or after a period of exclusion in patients with chronic
FPIES
• Repetitive profuse vomiting 90-100%
• Pallor 14-67%
• Lethargy 3-85%
• Hypotension 15%
• Onset 1-4 h
• Diarrhea onset 5-10 h
Michelet M, Schluckebier D, Petit LM, Caubet JC. Food protein-induced enterocolitis syndrome – a review of the literature with focus on clinical management. J
Asthma Allergy. 2017; 10: 197–207

34. Food Protein-Induced Enterocolitis Syndrome
• Chronic
• Chronic intermittent emesis
• Diarrhea with blood or mucus
• Abdominal distension
• Lethargy
• Severe case – dehydration, metabolic abnormalities, nutritional deficiency,
failure to thrive
Michelet M, Schluckebier D, Petit LM, Caubet JC. Food protein-induced enterocolitis syndrome – a review of the literature with focus on clinical management. J
Asthma Allergy. 2017; 10: 197–207

35. Pathophysiology
• Suggested T cells role
• Positive patch test
• Positive lymphocyte transformation test
• Local inflammation and ↑intestinal permeability
• TNF-α, IFN-γ, IL-9
• Lack of expression of TGF-β
Michelet M, Schluckebier D, Petit LM, Caubet JC. Food protein-induced enterocolitis syndrome – a review of the literature with focus on clinical management. J
Asthma Allergy. 2017;10: 197–207

36. Caubet JC, Bencharitiwong R, Ross A, Sampson HA, Berin MC, Nowak-Węgrzyn A. Humoral and cellular responses to casein in patients with food protein–induced
enterocolitis to cow's milk. J Allergy Clin Immunol. 2017 Faburary;139(2):572-83

37. Pathophysiology
• Neutrophil involvement
• ↑Serum IL-8 after positive OFC
• Increase after ingestion of food and peak at 6 h
• Neutrophil found in gastric aspirate, stool mucus, biopsies
• ↑ baseline serum tryptase levels
• Low-grade intestinal mast cell activation or increased mast cell load
• Paucity of humoral response
Michelet M, Schluckebier D, Petit LM, Caubet JC. Food protein-induced enterocolitis syndrome – a review of the literature with focus on clinical management. J
Asthma Allergy. 2017; 10: 197–207

38. Michelet M, Schluckebier D, Petit LM, Caubet JC. Food protein-induced enterocolitis syndrome – a review of the literature with focus on clinical management. J
Asthma Allergy. 2017; 10: 197–207

39. Michelet M, Schluckebier D, Petit LM, Caubet JC. Food protein-induced enterocolitis syndrome – a review of the literature with focus on clinical management. J
Asthma Allergy. 2017; 10: 197–207

40. Acquisition of Tolerance
Population Allergens % resolved Age
American Cow’s milk 20 3 year
Korean >60 10 months
Israeli 90 30 months
American Soy 20 3 year
Korean 90 10 months
American Grains 65 5 year
Meat 50 5 year
Fish/shellfish 50 5 year
Michelet M, Schluckebier D, Petit LM, Caubet JC. Food protein-induced enterocolitis syndrome – a review of the literature with focus on clinical management. J
Asthma Allergy. 2017; 10: 197–207

41. Protein-Induced Proctitis/Proctocolitis
• Benign transient condition
• Onset usually 1-4 weeks (days to 6 months)
• Blood streaked stools in well-appearing infant
• Offending foods
• Cow’s milk, soy (can be from mother)

42. Protein-Induced Proctitis/Proctocolitis:
Diagnosis
• History of rectal bleeding
• Response to an elimination diet

43. Food Protein-Induced Enteropathy
• Symptoms
• Malabsorption, intermittent vomiting, diarrhea, failure to thrive, rarely bloody
stools
• Less seen lethargy, pallor, dehydration, abdominal distension, hypotension,
hypothermia
• Similar to celiac disease
• Offending food – cow’s milk, soy, eggs, rice, poultry, fish, shellfish
• Diagnosis
• Clinical features
• Biopsy of the proximal small intestine
Morita H, Nomura I, Matsuda A, Saito H, Matsumoto K. Gastrointestinal Food Allergy in Infants. Allergol Int. 2013;62:297-307

44. Celiac Disease
• Autoimmune disorder
• Genetically predisposed + immune reaction to gluten
• Clinical manifestation
• Intestinal
• Extra-intestinal
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancete. 2018 January 6;391:70-81

45. Pathogenesis: Gluten
• Enriched in glutamines + prolines
• Incompletely digested by gastric, pancreatic, and brush border peptidases
• Leaving large peptides up to 33 amino acids long
Lamina propria
gliadin ↑immunogenicity
deamination
transglutaminase
Bind to HLA-DQ2, HLA-DO8
Gliadin-reactive CD4+ T cells
Ab against TTG, gliadin, actin
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancete. 2018 January 6;391:70-81

46. Innate Immune Response
• Prominent intraepithelial lymphocytosis
• Express receptors NKG2D and CD9/NKG2A
• Upregulated by IL-15
Product of stress-induced gene MICA and MICB and HLA-E
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancete. 2018 January 6;391:70-81

47. Genetic Factors
• Almost 100% - HLA-DQA1 and HLA-DQB1
• DQA1*05 + DQB1*02  DQ2 90%
• DQA1*03 + DQB1*0302 DQ8 10%
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancete. 2018 January 6;391:70-81

48. Clinical Manifestations
• Chronic diarrhea
• Weight loss
• Failure to thrive (rare)
• Iron deficiency
• Bloating
• Constipation
• Chronic fatique
• Headache
• Abdominal pain
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancete. 2018 January 6;391:70-81

49. Clinical Manifestations
• Diarrhea
• Bulky, foul-smelling, floating stools
• Malabsorption
• Growth failure
• Weight loss
• Anemia
• Neurologic disorder (vitamin B)
• Osteopenia (vitamin D, calcium)
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancete. 2018 January 6;391:70-81

50. Nongastrointestinal Manifestations
• Neuropsychiatric disease
• Headache
• Peripheral neuropathy
• Ataxia
• Depression, dysthymia, anxiety, epilepsy
• Arthritis
• Iron deficiency
• Occult GI bleeding may not be a major contributor
• 20% nonresponders to supplemental iron
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancete. 2018 January 6;391:70-81

51. Nongastrointestinal Manifestations
• Metabolic bone disease
• Hyposplenism
• Kidney disease – 1/3 IgA nephropathy
• Idiopathic pulmonary hemosiderosis
• Recurrent alveolar hemorrhage
• Lane-Hamilton syndrome
• Gluten-free diet associated with remission
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancete. 2018 January 6;391:70-81

52. Celiac Disease: Malignancy
• T-cell lymphoma
• Non-Hodgkin lymphoma
• Adenocarcinoma of esophagus, small intestine, colon, liver, pancreas
• Decreased
• Breast
• Lungs
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancete. 2018 January 6;391:70-81

53. Celiac Disease: Diagnosis
• Serology testing
• IgA-TTG antibodies
• Anti-endomysial antibodies
(EMA)
• Antigliadin antibody: anti-
deamidated gliadin peptide, anti
gliadin
• Duodenal biopsy
Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancete. 2018 January 6;391:70-81
UpToDate. drawing of the characteristic histologic changes seen in celiac disease as described by Marsh [Image on Internet]. 2018 Nov 28. Available from:
https://www.uptodate.com/contents/image?imageKey=GAST%2F60343&topicKey=GAST%2F4771&source=see_link

54. Diagnosis

55. IgE Mediated Presentations
• The history of an immediate reaction consisting of typical allergic
symptoms
• Test
• Skin prick tests with a commercial wheat extract
• Wheat-specific IgE
• In unclear cases
• Elimination of wheat
• Oral food challenge
Ho MH, Wong WH, Chang C. Clinical spectrum of food allergies: a comprehensive review. Clin Rev Allergy Immunol. 2014 Jun;46(3):225-40

56. Nowak-Wegrzyn A, Burks AW, Sampson HA. Reactions to foods. In: Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s
allergy principles and practice. Philadelphia; Elsevier Saunders; 2014. 1095-105

57. Wheat-Dependent Exercise-Induced Anaphylaxis
• SPT
• Wheat flour Sensitivity 94% Specificity 96%
• Gluten Sensitivity 100% Specificity 96%
• Specific IgE
• Wheat Sensitivity 81% Specificity 87%
• Gluten Sensitivity 100% Specificity 95%
• ω5-gliadin Sensitivity 100% Specificity 97%
Brockow K, Kneissl D, Valentini L, Zelger O, Grosber M, Kugler C, et al. Using a gluten oral food challenge protocol to improve diagnosis of wheat-dependent exercise-
induced anaphylaxis. J Allergy Clin Immunol. 2015 April;135(4):977-84

58. Baker’s Asthma
• Gold standard – inhalational challenge with wheat and rye flours
• . Specific IgE SPT
• Wheat PPV 74-100% 74-100%
• Rye PPV 82-100% 91-100%
• Cut-off 2.32 kU/L 5 mm
• . 9.64 kU/L 4.5 mm
van Kampen V, Rabstein S, Sander I, Merget R, Brüning T, Broding HC. Prediction of challenge test results by flour-specific IgE and skin prick test in symptomatic bakers.
Allergy. 2008;63(7):897

59. • Tested for sensitization to other grains
• OFCs may need to be performed to confirm clinical reactivity

60. Management

61. van Kampen V, Rabstein S, Sander I, Merget R, Brüning T, Broding HC. Prediction of challenge test results by flour-specific IgE and skin prick test in symptomatic bakers.
Allergy. 2008;63(7):897
Evaluate patients at regular intervals to determine whether she or he is still allergic