Tree nut allergy Presented by Rapisa Nantanee, M.D. August28, 2020

1. Tree Nut Allergy
Topic Review
August 28th, 2020
Rapisa Nantanee, M.D.
Pediatric Allergy and Immunology Unit
King Chulalongkorn Memorial Hospital

2. Outline
• Introduction
• Prevalence
• Co-allergies Patterns among
Nuts
• Allergens
• Effects of Processing on the
Allergenicity
• Clinical Manifestations
• Diagnosis
• Cross Reactivity
• Natural History
• Treatment

3. Introduction
• Nut is a culinary term used to describe any large, oily kernels
found within a shell and used in food.
• The term “tree nut” is commonly used to describe any nut
coming from a tree, and this includes foods that do not meet
the botanical definition.
• One of the eight most common allergens, and allergic reactions
to them can be severe.
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.
T. Weinberger, S. Sicherer. Journal of Asthma and Allergy 2018:11 41–51.

4. Introduction
• Nine nuts account for the majority of allergies to TNs, including
walnut, almond, pistachio, cashew, pecan, hazelnut,
macadamia, Brazil nut, and pine nut.
• For the purpose of labeling laws, the US FDA additionally considers
the following to be TNs: beechnut, butternut, chestnut, chinquapin,
coconut, ginkgo nut, hickory nut, lychee nut, pili nut, and shea nut.
• A report from the National Academies of Sciences recommends that
these nuts be removed from this list since there are little data on them
and they uncommonly cause allergic reactions.
T. Weinberger, S. Sicherer. Journal of Asthma and Allergy 2018:11 41–51.

5. This Photo by Unknown Author is licensed
under CC BY-NC
Walnut
This Photo by Unknown Author is
licensed under CC BY-NC
Almond
This Photo by Unknown Author is licensed
under CC BY-NC
Pistachio
This Photo by Unknown Author is licensed
under CC BY-NC
Cashew
https://thefineharvest.co.uk/product/sunburst-
whole-raw-pecan-nuts/
This Photo by Unknown Author is licensed
under CC BY-SA
Pecan
Hazelnut
This Photo by Unknown Author is licensed
under CC BY-SA
Macademia
Brazil nut
https://www.123rf.com/photo_121242354_pi
ne-nut-cone-and-pine-nuts-on-the-white.html
Pine nut
https://www.hmart.com/evergreen-0038

6. V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.
Prevalence

7. Prevalence
• Gene-environment interaction for food allergy risk
• In 3 separate Australian cohorts, the prevalence of food or nut allergy is
highest in children with Asian born parents compared with those with
Australian-born parents.
• In contrast, children who were born in Asia and migrated to Australia in
childhood had the lowest prevalence of food or nut allergy.
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

8. Parental migration from Asia to Australia appears to be an
important risk factor in the development of nut allergy in
the next generation, while being born in Asia is
protective even with migration to Australia in early life.
M. Panjari, et al. Clinical & Experimental Allergy, 2016 (46) 602–609.

9. Prevalence: Individual tree nuts
• Wide variation reported by region
• European studies report hazelnut as the most common tree nut allergy.
• Because of the high rate of birch pollen allergy and its cross-reactivity with hazelnut.
• United Kingdom - Brazil nut
• Australia - cashew
• The United States
• Previous studies had reported walnut and cashew as the most common tree nut
allergies.
• However, more recent survey data reports almond (0.7%) and cashew (0.7%) as the
most common.
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

10. Co-allergies Patterns among Nuts
• High sequence identity is found between tree nuts and even
between tree nut and some legumes (peanut) and seeds,
resulting in high rates of reported co-sensitization.
• Peanut and Tree Nut Co-allergy
• Tree Nut Co-allergy
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

11. Peanut and Tree Nut Co-allergy
• In vitro cross-reactivity between peanuts and tree nuts has
been reported as high as 86%, and tree nut sensitization among
those with peanut allergy as high as 87%.
• The coexistence of clinical peanut and tree nut allergy is lower,
with estimates based on self-report between 20% and 60%.
• Studies based on OFC-confirmed outcomes report much
lower rates: 4 – 40%.
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

12. Tree Nut Co-allergy
• Higher levels of co-sensitization and lower rates of clinical
allergy
• Highlighting the limitation of relying on sensitization data alone
• A single-center retrospective US study of 159 tree nut challenges
performed in tree nut-sensitized individuals found a co-allergy rate of
24% to 1 or more tree nuts.
• Australian HealthNuts study, with a co-allergy rate of 47% reported.
• The OFC data for the full range of tree nuts were limited.
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

13. Tree Nut Co-allergy
• The strongest cross-reactivities among tree nuts appear to
follow botanical family associations.
• Walnut-pecan in the Juglandaceae family
• Cashew-pistachio in the Anacardiaceae family
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

14. S. Bastiaan-Net, et al. Int Arch Allergy Immunol 2019;178:19–32.

15. S. Bastiaan-Net, et al. Int Arch Allergy Immunol 2019;178:19–32.

16. Tree Nut Co-allergy
• Tree nut co-sensitizations are common, and distinguishing
asymptomatic sensitization from clinical food allergy is reliant on
resource-intensive and potentially risky food challenges.
• Where knowledge of individual tree nut allergy or tolerance is
established, avoidance or inclusion of specific nuts can be difficult
because of current food product labeling practices adopting the
generic term tree nuts in ingredients lists and precautionary allergen
statements rather than specifying the individual nuts.
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

17. Co-allergies Patterns
among Nuts
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

18. Tree Nut Allergens
• Seed storage proteins
• 2S albumins (10-16 kDa)
• Legumins – 7S globulins
• Vicilins – 11S globulin (50 kDa)
• Pathogenesis-related (PR)
proteins
• PR-10 (Bet v 1-like)
• PR-14 - Non-specific (ns) lipid
transfer protein (nsLTP)
• Oil-body associated oleosins
• Profilin
E. Knol, M. Wickman. EAACI Molecular Allergology User’s Guide. 2016.
The allergenic proteins, with the
exception of profilin and
pathogenesis-related 10 (PR-
10) allergens, in tree nuts are
heat stable.

19. E. Knol, M. Wickman. EAACI Molecular Allergology User’s Guide. 2016.
2S albumin
proteins can be
potent allergens
and are related to
the more severe
forms of allergy
The prominent PR-
10/Bet v 1 family is
only described in the
hazelnut as Cor a 1,
but this allergen has
not been described
(yet) in the other tree
nuts.

20. L. J. Masthoff, et al. Allergy 2013; 68: 983–993.

21. Processing effects on tree nut allergens
• Processing techniques
• Thermal processing
• Mechanical processing
• Chemical processing
• Irradiation of food
S. K. Vanga, V. Raghavan. Critical Reviews in Food Science and Nutrition, 57:17, 3794-3806, 2017.

22. Processing effects on tree nut allergens
• Thermal treatments
• Moist heating (Boiling, Autoclaving), dry heating, dielectric heating
(Microwave and Radio frequency processing)
• Conformational changes in the secondary structures of the protein,
which will influence their functional properties.
• On further increasing the temperature (>100oC), chemical reactions
take place in protein which can involve covalent bond formation. due
to protein interactions with sugars and lipids present in the food matrix
(Example: Maillard reaction).
S. K. Vanga, V. Raghavan. Critical Reviews in Food Science and Nutrition, 57:17, 3794-3806, 2017.

23. L. J. Masthoff, et al. Allergy 2013; 68: 983–993.

24. L. J. Masthoff, et al. Allergy 2013; 68: 983–993.

25. L. J. Masthoff, et al. Allergy 2013; 68: 983–993.

26. L. J. Masthoff, et al. Allergy 2013; 68: 983–993.

27. Clinical manifestations
• Reactions to TNs can be severe.
• Peanut and TNs account for 70%–90% of reported food-related
anaphylactic fatalities, and TNs alone account for 18%–40% of cases
of anaphylaxis.
• Pollen food allergy syndrome
• An IgE-mediated allergy due to cross-reacting homologous proteins in
pollens and various foods, including nuts, fruits, and vegetables
• Birch-pollen-sensitized individuals may develop PFS upon the
ingestion of almond and hazelnut.
T. Weinberger, S. Sicherer. Journal of Asthma and Allergy 2018:11 41–51.

28. Diagnosis
• A combination of a thorough clinical history, serum-specific IgE, skin prick testing
(SPT), and OFCs
• TN-specific skin tests and serum IgE are markers of sensitization and can help
aid in the diagnosis when there is clinical suspicion.
• In a cross-sectional, observational study in the UK, of 1,000 children and adults referred
to an allergy clinic with a history of reaction to TNs or peanut, an SPT of ≥8 mm to TNs
predicted clinical reactivity with >95% accuracy.
• An Australian prospective study, in which 247 patients with concern for TN allergy
underwent OFC, confirmed that an SPT ≥8 predicted clinical reactivity for cashew,
hazelnut, and walnut.
• Skin tests can vary widely among patients, institutions, and the extracts used.
Therefore, each practitioner must interpret SPT values somewhat cautiously.
T. Weinberger, S. Sicherer. Journal of Asthma and Allergy 2018:11 41–51.

29. Diagnosis
• TN sIgE
• The UK observational study mentioned above found that a level of ≥15 kU/L to an
individual TN had a 95% PPV for clinical allergy.
• In the study by Fleischer et al, 63% patients with TN sIgE levels of <2 kUA/L passed
challenges.
• In a retrospective US study reviewing open TN OFCs, 79 of 124 (89%) patients
passed a challenge with a TN-specific IgE level <2 kUA/L, whereas 10 of 16 (69%)
patients passed an OFC with a TN sIgE level of ≥2 kUA (mean =5.12 kUA/L).
• Overall, a SPT ≥8 mm or TN sIgE ≥15 kU/L usually indicates a high
risk of allergy.
T. Weinberger, S. Sicherer. Journal of Asthma and Allergy 2018:11 41–51.

30. Diagnosis: Oral Food Challenge
• Double-blind, placebo-controlled food challenges remain the
gold standard for diagnosis.
• But are resource-intensive and not typically indicated for diagnosis
where there is a clear history of recent reaction.
• For those with established allergy
• OFC may be used to determine reaction thresholds or
• for commencement of oral immunotherapy trials or treatment
• There is a need for better minimally invasive diagnostic tools for
tree nut allergy diagnosis and management.
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

31. Diagnosis:
Component-resolved diagnostics (CRDs)
• Or molecular allergen analysis
• While serum-specific IgE measures IgE to the whole food
extract, CRD measures IgE to specific proteins within that
food.
• Potential to improve the diagnostic accuracy of specific
tree nut allergy
• Limited studies have validated the use of CRD for tree nuts.
T. Weinberger, S. Sicherer. Journal of Asthma and Allergy 2018:11 41–51.
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

32. Diagnosis:
Component-resolved diagnostics (CRDs)
• Hazelnut
• Using CRD for hazelnut allergy with Cor a 9 and Cor a 14 hazelnut
storage proteins increased diagnostic specificity compared with
hazelnut sIgE in children.
• Differentiating primary hazelnut allergy from sensitization to birch.
• Region specific, with differential thresholds for Cor a 14
• ≥ 1.0 kUA/L, with a sensitivity of 92% and specificity of 93%, in the United States
• ≥ 5.0 kUA/L with a sensitivity of 83% and specificity if 93%, in the Netherlands
• ≥ 0.35 kUA/L with a sensitivity of 85% and specificity of 81%
• for the diagnosis of hazelnut allergy.
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

33. Diagnosis:
Component-resolved diagnostics (CRDs)
• Ana o 3 for cashew allergy (93% of allergic children)
• Pis v 1 for pistachio (68% pistachio allergic patients)
• Jug r 1 for walnut (75% walnut-allergic patients)
• Car i 2 for pecan (24% pecan-allergic patients)
• Clinical reactivity for other tree nut allergens such as pine nut,
Brazil nut, and macadamia have not yet been described.
• With the use of CRD, several tree nuts could be
reintroduced to the diet of those allergic to peanut.
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

34. Diagnosis: Basophil activation test
(BAT)
• Uses flow cytometry to measure the expression of activation
markers on the surface of basophils in the presence of allergen,
have been explored for the diagnosis of tree nut allergy.
• The NUTCRACKER study found that
• SPT and BAT separately were limited in their ability to distinguish
allergy from tolerance,
• but used BAT in combination with SPT and found BAT correctly
differentiated co-allergenicity patterns in patients sensitized to walnut,
pecan, cashew, and pistachio.
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

35. Diagnosis: Pollen food syndrome
(PFS)
• Characterized by
• seasonal allergic rhinitis and
• a history of reactions to fresh fruit, vegetables or nuts.
• Symptoms are typically mild and isolated to the oropharynx.
• Anaphylaxis can occur but is uncommon.
• Serum specific IgE is directed against heat-labile proteins (PR-
10 homologues) homologous to those in pollen.
G. Stiefel, et al. Clin Exp Allergy. 2017;47(6): 719-739.

36. Cross-reactivity
• Bioinformatics approaches have been implemented to compare seed
storage allergen protein sequences and predict cross-reactivity
based on homology.
• For example, modelling studies have been performed to map the linear IgE-
binding epitopes for walnut and hazelnut 11S globulins and compare them to
other allergens, including cashew, peanut and soybean.
• Some structural homology was observed between surface-exposed
epitopes, which could contribute to the cross-reactivity seen between
peanut and tree nut allergens, despite not belonging to the same botanical
family.
J. M. Smeekens, K. Bagley, M. Kulis. Clin Exp Allergy. 2018;48:762–772.

37. Cross-reactivity
• After a thorough comparison of structural properties of
allergens, Aalberse suggests that at least 70% overlap is
required for cross-reactivity to take place.
• IgE-binding epitope regions need to be taken into account when
interpreting sequence identities.
J. M. Smeekens, K. Bagley, M. Kulis. Clin Exp Allergy. 2018;48:762–772.

38. J. M. Smeekens, K. Bagley, M. Kulis. Clin Exp Allergy. 2018;48:762–772.

39. J. M. Smeekens, K. Bagley, M. Kulis. Clin Exp Allergy. 2018;48:762–772.

40. J. M. Smeekens, K. Bagley, M. Kulis. Clin Exp Allergy. 2018;48:762–772.

41. Cross-reactivity
• There is high sequence identity between tree nuts, and even
between tree nuts and some legumes and seeds, resulting in
potential cross-reactivity between these allergens.
• It is currently unclear the extent of similarities required to
warrant true cross-reactivity at the IgE or T-cell level.
J. M. Smeekens, K. Bagley, M. Kulis. Clin Exp Allergy. 2018;48:762–772.

42. Natural History
V.L. McWilliam et al. Ann Allergy Asthma Immunol 124 (2020) 466 - 472.

43. Management
P. A. Eigenmann, et al. J Allergy Clin Immunol Pract 2017;5:296-300.

44. E. Knol, M. Wickman. EAACI Molecular Allergology User’s Guide. 2016.

45. Thank you for your attention