Wheal Allergy Presented by Lalita tearprasert, MD. November17, 2015

1. Wheat Allergy
Lalita Tearprasert; M.D.

2. • Prevalence
• Wheat proteins and allergens
• Cross-reactivity
• Clinical manifestations
• Wheat allergy and others allergy
• Diagnosis of wheat allergy
• Natural history
• Management
• Specific oral tolerance induction (SOTI)
Scope

3. Food Allergy : Top 8
90% of food allergy

4. Reactions to foods. Middleton's 8th Edition. 1310-39.
Prevalence of wheat
allergy
• Varies depending on age and region : 0.4-1%
M. J. Makela et al. Clinical & Experimental Allergy, 2014 (44) 1420–1430.

5. • In Asia
- Marked differences in prevalence
- Prominent in Japanese school children (unknown reason)
0.21% in Japanese adults
- Increasingly reported in Thailand
• Most common cause of food dependent exercise-anaphylaxis
(FDEIA) in Japan and Korea
Lee AJ, et al. Asia Pacific Association of Allergy, Asthma and Clinical Immunology 2013.
Prevalence of wheat
allergy

6. Urisu A et al. Japanese Guideline for Food Allergy 2014.
Japan

7. Urisu A et al. Japanese Guideline for Food Allergy 2014.

8. Lee AJ, et al. Asia Pacific Association of Allergy, Asthma and Clinical Immunology 2013.
0.08-0.37%
0.22-0.5%
Korea
UK
USA
Japan

9. Thailand
• The prevalence of wheat allergy was 4.85% (unpublished data).
• During 1998-2005
• 103 patients who had a history of food allergy
• At Allergy Clinic, Department of Pediatrics, Siriraj Hospital
Pacharn, Et al. Asian Pacific Journal Of Allergy And Immunology (2009) 27: 115-120.

10. Wheat proteins
& Allergens

11. Taxonomy of Wheat
D.-A. Moneret-V autrin. Et al. Eur Ann Allergy Clin Immunol. Vol 40, N 3, 67-76, 2008.
Durum wheat is very rich in gluten
>> used to produce semolina flour
and pasta products

12. Wheat grain Wheat proteins

13. Water/ Salt-soluble
1.) Albumins : Water - soluble
2.) Globulins : Salt - soluble
3.) Gliadins (Prolamins) : Ethanol - soluble
4.) Glutenins : Alkali/Acid - soluble
Water/ Salt-insoluble
Osborne T. The proteins of the wheat kernel. Washington DC: Carnegie Inst.1907,84.
D.-A. Moneret-V autrin. Et al. Eur Ann Allergy Clin Immunol. Vol 40, N 3, 67-76, 2008.
A.S. Tatham & P. R. Shewry. Clinical and Experimental Allergy, 38, 1712–1726.
Gluten
Wheat proteins
• T.B. Osborne developed a classification (Osborne fractions)
>> based on their solubility

14. M. J. Makela et al. Clinical & Experimental Allergy, 2014 (44) 1420–1430.
D.-A. Moneret-V autrin. Et al. Eur Ann Allergy Clin Immunol. Vol 40, N 3, 67-76, 2008.
Water/ Salt - soluble
Albumins, Globulins
• Most important allergen in this
group
• Associated with
- Baker's asthma (adults)
- Food allergy in atopic
dermatitis (children)
Alpha-amylase inhibitor
(AAI)

15. Nonspecific lipid transfer proteins
(LTP)
• Wheat LTP (Tri a 14)
• 24/40 patients (60%) of baker's asthma sensitized to wheat
strongly recognized specific IgE to Tri a 14
• Major inhalant allergen associated with baker's asthma
• Peach LTP, Pru p 3, showed a sequence identity of 45%, but
the low cross-reactivity between both allergens
Palacin et al. J Allergy Clin Immunol 2007;120:1132-8.

16. Gluten
• Form a continuous network when wheat flour is mixed with water
to form dough and processed into bread, noodles and other foods.
• Comprises approximately equal amounts of the gliadin and glutenin
A.S. Tatham & P. R. Shewry. Clinical and Experimental Allergy, 38, 1712–1726.
Water/ Salt - insoluble
Gluten

17. A.S. Tatham & P. R. Shewry. Clinical and Experimental Allergy, 38, 1712–1726.
Palosuo et al. J Allergy Clin Immunol 2001;108:634-8.
Fast
Intermediate
Slow
Severe allergic reactions (WDEIA or WIA) associated with
1.) Omega-5 gliadin (Tri a 19)
2.) High-molecular-weight glutenin subunits
• Triggering Coeliac disease

18. Omega-5-gliadin (Tri a19)
• Related to the immediate symptoms after ingestion of wheat
in wheat-sensitized children
• Associated with a strong convincing history of wheat anaphylaxis
• Risk marker for clinical reactivity
• Associated with severe allergic reactions
- Wheat-induced anaphylaxis (WIA)
- Wheat-dependent exercise-induced anaphylaxis (WDEIA)
Ito et al. Allergy 2008: 63: 1536–1542.
Palosuo et al. J Allergy Clin Immunol 2001;108:634-8.

19. • Associated with
>> WDEIA symptoms in patients that do not have IgE
antibodies to omega-5-gliadin
>> Marker of severity of oral wheat challenge
Ito et al. Allergy 2008: 63: 1536–1542.
M. J. Makela et al. Clinical & Experimental Allergy, 2014 (44) 1420–1430.
High molecular weight glutenin
(HMW)

20. Wheat allergens
2015 : 27 allergens

21. 2015 : 27 allergens
(15 Food allergens)

22. Alpha-Purothionin (Tri a 37),
a new wheat allergen associated
with severe allergy
• Novel water- and salt-soluble wheat food allergen in
the albumin/globulin fraction
• Frequently recognized by patients with severe anaphylactic
reactions to wheat
• Represent a diagnostic marker for an increased risk of
wheat-induced anaphylaxis
J Allergy Clin Immunol. October 2013. Volume 132, Number 4.

23. IgE reactivity to Tri a 37 was highly specific for wheat food allergy because patients
with grass pollen allergy and nonallergic subjects did not show IgE reactivity
J Allergy Clin Immunol. October 2013. Volume 132, Number 4.
Food allergy
Grass pollen allergy
Nonallergic

24. • The sequence identity of Tri a 37 from wheat, rye, and barley
was high (ie, >80%), whereas from oat, rice, and other plants
showed a much lower sequence identity of 50% or less
J Allergy Clin Immunol. October 2013. Volume 132, Number 4.

25. Baker's asthma WIA, WDEIA
- 1.) Alpha - amylase inhibitor
- (water/salt soluble)
- 1.) Omega-5-gliadin (Tri a 19)
- (water/salt insoluble)
- 2.) Nonspecific lipid transfer
- proteins/ LTP (Tri a 14)
- (water/salt soluble)
- 2.) High molecular weight
- glutenin/ HMW
- (water/salt insoluble)
- 3.) Alpha-Purothionin (Tri a 37)
- (water/salt soluble)

26. Cross-reactivity

27. Sampson et al. Food allergy. Practice parameter 2014.
Cross-reactivity among
grains

28. - Rye : γ-70 and γ-35 secalins
- Barley : γ-3 hordein
wheat : ω-5 gliadin
K. Palosuo et al. Clinical and Experimental Allergy, 2001, Volume 31, pages 466-473.
Rye Barley
WheatWheat
Wheat & Rye, Barley
23 patients with WDEIA showed IgE binding
- 21 (91%) to g-70 secalins
- 19 (83%) to g-35 secalins
- 21 (91%) to g-3 hordein
Cross-reactivity
WDEIA

29. Cross-reactivity
between grains & grass
Family Poaceae
Jones et al. J Allergy Clin Immunol 1995;96:341-51.

30. Jones et al. J Allergy Clin Immunol 1995;96:341-51.

31. • Patients with IgE-mediated wheat allergy alone show extensive
in vitro cross-reactivity to other cereal grains and grass pollens
• However, clinical cross-reactivity to multiple cereal grains occurs
in a minority of patients sensitized to multiple grains
• Elimination of all grains (eg, wheat, rye, barley, oats, rice, and corn)
from the diet of a patient with grain allergy is not recommended and
might be nutritionally harmful.
Sampson et al. Food allergy. Practice parameter 2014.

32. Clinical
manifestations

33. Clinical manifestations
• Clinical types of wheat allergies depend on
1.) Age
- Children : Atopic dermatitis (common)
- Adult : Anaphylaxis, WDEIA, Baker's asthma (common)
2.) Sensitization route
- Ingestion, Contact : AD, Anaphylaxis, WDEIA
- Inhalation : Baker's asthma, Rhinitis
Inomata N. Current Opinion in Allergy and Clinical Immunology 2009, 9:238–243.
D.-A. Moneret-Vautrin. Et al. Eur Ann Allergy Clin Immunol. VOL 40, N 3, 67-76, 2008.

34. • IgE-mediated immediate symptoms
(within minute - 2 hr. after ingestion)
- Skin : Urticaria, Angioedema
- Respiratory : Wheezing
- GI : Vomiting, Abdominal pain
- Atopic dermatitis
- Anaphylaxis
• Delayed reaction
- Worsening of atopic dermatitis
- GI symptoms
Palosuo K. Update on wheat hypersensitivity. Curr Opin Allergy Clin Immunol 2003: 3: 205–9.

35. Keet et al. RA. Ann Allergy Asthma Immunol. 2009;102:410–415.
• Johns Hopkins Pediatric Allergy Clinic from 1993 to 2007
• 103 patients with IgE-mediated wheat allergy
76/103 (86%) : ingestion
12/103 (14%) : contact, inhalation

36. • One of the most common forms of occupational asthma
• 4-10% of bakery workers in European countries
• Mostly sensitized to raw flour particles inhaled via the respiratory mucosa
• Never have problems with ingestion of cooked wheat
• IgE-mediated
• Diagnosis : SPT, sIgE to wheat
• Allergen : alpha-amylase inhibitors
D.-A. Moneret-Vautrin. Et al. Eur Ann Allergy Clin Immunol. VOL 40, N 3, 67-76, 2008.
A.S. Tatham & P. R. Shewry. Clinical and Experimental Allergy, 38, 1712–1726.
Baker's Asthma

37. • 7 children (5 boys, 2 girls)
• Aged from 6 months to 13 years
• Department of Pediatrics, Siriraj Hospital in Bangkok
Daengsuwan et al. Allergy 2005: 60: 506–509.
Wheat-induced Anaphylaxis
Thailand

38. France
Moneret-Vautrin et al. Allergy 2005: 60: 443–451.
• Between 2002 and 2004
• Department of Internal Medicine, Clinical Immunology and
Allergology, University Hospital, Nancy Cedex, France

39. E. Morita et al. Journal of Dermatological Science (2007) 47, 109—117.
Food-dependent exercise-induced anaphylaxis
(FDEIA)

40. 100% 80%
• January 2002 - December 2006
• 5 Childrens with a Hx of WDEIA
• The mean ± SD of the patients'
age at the onset of the symptoms
was 11 ± 2.23 years (8-14 years)
Pacharn, et al. Asian Pacific Journal Of Allergy and Immunology (2009) 27: 115-120.

41. Wheat-dependent exercise-induced anaphylaxis
(WDEIA)
• Diagnosis
1.) History of ingestion & Exercise
2.) An exercise challenge test following wheat ingestion
(which is time-consuming and unsafe)
• Mechanism
1.) Activated tissue transglutaminase
2.) Increased absorption of allergens through GI tract
• Factor triggers
- Among of wheat ingested
- Degree of exercise
- Others : Aspirin, NSAIDs (COX-1 inhibitors)
Hae-Sim Park. Et al. Int Arch Allergy Immunol 2012;157:147–150.
Inomata N. Current Opinion in Allergy and Clinical Immunology 2009, 9:238–243.

42. Before tTG After tTG
Palosuo et al. J Allergy Clin Immunol 2003;111:1386-92.
Tissue transglutaminase (tTG)
• Enzyme in gut epithelium
• Released and activated after stress-liked condition
• Forming complex with digested gliadin

43. Digested gliadin forms peptide
Cross-linked to tTG
HMW complex
Strong binding serum IgE Ab
Palosuo et al. J Allergy Clin Immunol 2003;111:1386-92.

44. Inomata N. Current Opinion in Allergy and Clinical Immunology 2009, 9:238–243.
• Management & Prevention
1.) Avoidance of exercise for approximately 4 hr. after
ingestion of wheat
2.) Wheat should not be consumed for several hours
after intake of aspirin and other preferential COX-1 inhibitors
3.) Education : Reading food labels, Adrenaline autoinjection

45. Wheat allergy &
Other allergy

46. CDC/NCHS, National Health Interview Survey. October 2008.

47. Keet et al. RA. Ann Allergy Asthma Immunol. 2009;102:410–415.
90% allergic to at least
1 other food allergen
(Most common : Milk)
Most : Eczema

48. Most : Eczema
Most : Milk 80%
- In all the children other food
allergies had been diagnosed
before wheat
Czaja-Bulsa and Bulsa Allergy, Asthma & Clinical Immunology 2014,10:12.

49. Kotaniemi-Syrjanen et al. Pediatr Allergy Immunol 2010: 21: e421–e428.

50. Diagnosis
of wheat allergy

51. • Relation between food intake and symptoms
• Diagnostic testing
• Elimination diet
• Oral food challenge
How to diagnosis
?

52. Reactions to foods. Middleton's 8th Edition. 1310-39.
sIgE to wheat
• IgE levels have been regarded as a useful predictor of food challenge outcom
Ito et al. Allergy 2008: 63: 1536–1542.
Mixture of water/ salt soluble
wheat protein
Lack of gliadin fraction

53. Reactions to foods. Middleton's 8th Edition. 1310-39.
Cross-reactivity of
wheat allergens with
grasses

54. IgE antibodies to omega-5 gliadin
• Challenge positive children showed that with severe reactions
had significantly higher concentrations of specific IgE antibodies
to omega-5-gliadin compared with mild or moderate symptoms
(P < 0.001)
Ito et al. Allergy 2008: 63: 1536–1542.

55. Ito et al. Allergy 2008: 63: 1536–1542.
• Significantly higher concentrations of specific IgE antibodies to omega-5-gliadin
- Children with a positive challenge (P < 0.01)
- Children with a positive convincing history (P < 0.001)

56. Palosuo et al. J Allergy Clin Immunol 2001;108:634-8.
• 40 children (mean age, 2.5 years;
range, 0.7-8.2 years)
• Suspected wheat allergy
(AD and/or GI and/or respiratory symptoms)
• oral wheat challenge,
- 19 children (48%) : immediate
- 8 children (20%) : delayed hypersensitivity
• 16/19 (84%) of the children with immediate
symptoms had IgE antibodies to purified
ω-5 gliadin in ELISA

57. Hae-Sim Park. Et al. Int Arch Allergy Immunol 2012;157:147–150.

58. Hae-Sim Park. Et al. Int Arch Allergy Immunol 2012;157:147–150.
Serum IgE ratio of omega-5 gliadin to wheat may be a useful marker for the
diagnosis of WDEIA and WIA.
(Cutoff value = 0.3, Sensitivity & Specificity 100%)
Ratio of omega-5 gliadin to wheat

59. Palosuo et al. J Allergy Clin Immunol 2001;108:634-8.
Explained by the use of antigen extracts containing wheat proteins mainly
from the water/salt-soluble albumin and globulin fractions
rather than from the ethanol-soluble gliadin fraction
Predictive
capability

60. Wheat sIgE Omega-5 gliadin sIgE
Urisu A et al. Japanese Guideline for Food Allergy 2014.

61. Natural history

62. Rate of resolutions
Age
Rate of resolutions
Keel et al.
Ann Allergy Asthma Immunol, 2009
Czaja-Bulsa et al.
Ann Allergy Asthma Immunol, 2014
4 yrs. 29% 20%
8 yrs. 56% 52%
12 yrs. 65% 66%
18 yrs. - 76%
Keel et al. Ann Allergy Asthma Immunol, 2009.102:410–415.
Czaja-Bulsa et al. Ann Allergy Asthma Immunol, 2014.10:12.
Median age 6.5 yrs.

63. Predictors of
tolerance
1.) Peak wheat IgE
2.) Age of reaching peak wheat IgE
Keel et al. Ann Allergy Asthma Immunol, 2009.102:410–415.
Czaja-Bulsa and Bulsa Allergy, Asthma & Clinical Immunology 2014, 10:12.

64. Peak wheat IgE level &
Persistence of wheat allergy
Keel et al. Ann Allergy Asthma Immunol, 2009.102:410–415.
median age 31 mo.
median age 54 mo.
median age 145 mo.
P < 0.001

65. Czaja-Bulsa and Bulsa Allergy, Asthma & Clinical Immunology 2014,10:12.
Peak wheat IgE level &
Persistence of wheat allergy
Peak wheat IgE
(kU/L)
Median age of
tolerance (mo.)
< 10 41.4
10-19.9 44.5
20-49.9 84.9
50 up 190.5
80% of WT : peak wsIgE < 50 kU/L
40% of WT : peak wsIgE 50 kU/L up

66. Relationship of Wheat IgE level & Age
Keel et al. Ann Allergy Asthma Immunol, 2009.102:410–415.
In general, the peak wheat IgE level occurred before 4 years of age
Reaching peak wheat IgE in older age is an important factor increasing
the risk that the allergy will continue into adulthood
Czaja-Bulsa and Bulsa Allergy, Asthma & Clinical Immunology 2014,10:12.

67. Wheat IgE level & Resolution
• Higher wsIgE levels : a poorer prognosis
• Decreases in sIgE over time might signal resolution
Czaja-Bulsa and Bulsa Allergy, Asthma & Clinical Immunology 2014,10:12.
Sampson HA. et al. J Allergy Clin Immunol. Volume 133. Number 2. Febuary 2014.

68. • Compared with other food allergies, wheat specific IgE level is
less helpful in predicting clinical reactivity and prognosis
1.) No clear cutoffs for wheat IgE levels that predict clinical reactivity
2.) Grass pollens and wheat can be cross-reactive in vitro, creating
false-positive wheat IgE test results
3.) sIgE for wheat do not contain all the wheat grain allergens
• Children passed wheat challenges with even the highest levels of
wheat IgE
- 25% of children with a peak wheat IgE level more than 50 kU/L
outgrew their allergy
- 20% of children with a peak wheat IgE level more than 100 kU/L
outgrew their allergy
Keel et al. Ann Allergy Asthma Immunol, 2009.102:410–415.
Czaja-Bulsa and Bulsa Allergy, Asthma & Clinical Immunology 2014,10:12.

69. Management

70. • Wheat avoidance
• WDEIA
1.) Avoidance of exercise for approximately 4 hr. after
ingestion of wheat
2.) Wheat should not be consumed for several hours
after intake of aspirin and other preferential COX-1
inhibitors
• Education : Reading food labels, Adrenaline autoinjection
Management
Inomata N. Current Opinion in Allergy and Clinical Immunology 2009, 9:238–243.

71. Difficult to
Avoidance !!!
Foods containing/possibly
containing wheat

72. Urisu A et al. Japanese Guideline for Food Allergy 2014.

73. www.wholegrainscouncil.org.

74. Specific oral
tolerance induction
(SOTI)

75. Indication
1. Severe reactions to food proven by challenge
2. History of accidental exposures recently
3. Unable to avoid food on daily life
4. Age limit beyond natural acquisition of tolerance to
particular food
SOTI
Wheat
Accidental exposure frequently occurs since wheat is commonly
used in widely available processed foods
Age of natural tolerance to wheat is poorly defined
Pacharn P, et al. Asia Pacific Association of Allergy, Asthma and Clinical Immunology 2014.

76. • 20 children with a history of wheat allergy
(allergic episodes were confirmed within a year prior to the study entry)
• 13 male, 7 female, Age 4.1±2.3 years
• Divided into 3 group based on the value of ELISA of the hypoallergenic
wheat at the time of study entry
- Severe wheat allergy (group S) : IgE < 0.05 (8 children)
- Mild wheat allergy (group M) : IgE > 0.05 (7 children)
- No desensitization (group C) : 5 children
Taniuchi S. el al. The Journal of Applied Research. Vol.9 , No.4 , 2009.

77. Taniuchi S. el al. The Journal of Applied Research. Vol.9 , No.4 , 2009.
S group
M group
C group
"Twice - weekly dose"
at home

78. Results
• Group S
- 6/8 children (75%) : achieved a daily intake of 100g of wheat product
• Group M
- 5/7 (71.4%) : achieved the daily intake of 100g of wheat product
• Group C
- 4/5 (80%) : severe allergic reactions
Conclusions
• Hypoallergenic wheat is a useful food for inducing food tolerance of
wheat by oral desensitization for children with wheat allergy.
• Further study will be needed to evaluate the starting dose and the
frequency of ingestion of hypoallergenic wheat
Taniuchi S. el al. The Journal of Applied Research. Vol.9 , No.4 , 2009.

79. • 2 children with high wheat sensitivity (4 and 14 years old boys)
• Oral challenges indicated eliciting doses of 300 mg, and wheat flour
of 30 mg
• Multirush/ maintenance regimen
• OIT protocol
- 5 days of build-up phase in the hospital intervening
- 2 to 5 months of home maintenance phase
Pacharn P, et al. Asia Pacific Association of Allergy, Asthma and Clinical Immunology 2014.

80. Pacharn P, et al. Asia Pacific Association of Allergy, Asthma and Clinical Immunology 2014.
Patients could tolerate 45 g, and 60 g of wheat flour per day
40 g./ pack15 g./ piece

81. Thank you