Nut allergy

Athipat Athipongarporn
Division of Pediatric Allergy and Immunology
King Chulalongkorn Memorial Hospital
Everything you need to know about…

Contents
• Introduction and epidemiology
• Peanut allergy
• Other nut allergy
• CRD and cross reactivity
• Management and Prognosis
• Prevention

Introduction
• Nut allergy is the commonest cause of anaphylactic
death in adolescents and young adults
• Peanut and tree nut allergies can resolve, although
less commonly compared with other food allergies
John Wiley & Sons Ltd, Clinical & Experimental Allergy.2017.47 : 719–739
Edward Knol, Magnus Wickman.EAACI Molecular Allergology User´s Guide.2016

Peanut
Arachis hypogaea
• Family Fabaceae
• Other name: Groundnut, goober, or
monkey nut (UK)
• Domesticated in Paraguay or Bolivia
around seven thousand years ago
• Cultivated throughout the tropical
and warm-temperate zones
https://www.cabi.org/isc/datasheet/6932

Tree nut
• Tree nuts grow on trees
• Tree nuts include almonds, Brazil nuts, cashews,
hazelnuts, pecans, pistachios and walnuts

Almond
Prunus dulcis
Brazil nuts
Bertholletia excelsa
Cashews
Anacardium occidentale
Hazelnuts
Corylus avellana

Pecans
Carya illinoinensis
Pistachios
Pistacia vera
Walnuts
Juglans regia

Almond
Prunus dulcis
• Family: Rosaceae
• Habitat : Cultivated ground, thickets,
hedges and rocky places near cultivation
• Native to Mediterranean climate
• Thrives in a well-drained moisture-
retentive loamy soil
• “Amygdaloid" = "like an almond“
• Food
• Cakes and biscuits, to crunchy roasted
chopped almonds in salads and soups
https://pfaf.org/user/plant.aspx?LatinName=Prunus+dulcis

Brazil nuts
Bertholletia excelsa
• Other name: para nut
• Order Ericales: Blueberries, cranberries
• Native to the Guianas, Venezuela, Brazil,
eastern Colombia, eastern Peru
• The fruits are very heavy and rigid
• Between 12 and 25 seeds are enclosed
inside the large, round fruits
• Food
• Baking and go well with chocolate
• Brazil nut oil
https://www.arkive.org/brazil-nut tree/bertholletia-excelsa/

Cashews
Anacardium occidentale
• Family: Anacardiaceae
• Originally native to northeastern Brazil
• Cashew seed (nut) and the cashew
apple ("sweet" smell and taste)
• Caschew nut and shell
• The shell of the cashew nut contains
oil compounds which may cause
contact dermatitis
http://rfcarchives.org.au/Next/Fruits/Cashew.Cashew5-87.htm

Hazelnuts
Corylus avellana
• Family: Betulaceae
• Genus Corylus
• Other name: cobnut or filbert nut
• Found in a midden pit on the
island of Colonsay in Scotland
• Food
• Combination with chocolate for
chocolate truffles (Nutella, Ferrero
Rocher)
https://www.ancestry.com/name-origin?surname=hazel

Pecans
Carya illinoinensis
• Family : Juglandaceae
• Native to northern Mexico and the
southern United States
• Food
• Eaten raw, sweetened or salted.
• Coffee cakes
• Chocolate
https://www.britannica.com/plant/pecan

Pistachios
Pistacia vera
• Family Anacardiaceae
• Genus Pistacia
• Originating from Central Asia
• Food
• fresh salads
• Cakes
http://www.newworldencyclopedia.org/entry/Pistachio

Walnuts
Juglans regia
• Family Juglandaceae
• Native to eastern North America
(Black walnut)
• Asia stretching from the Balkans to
China
• Food
• Salad,Coffee cake
• Nut oil
• Nonfood
• Folk medicine
• Walnut ink
http://www.fruitandnut.ie/walnuts.html

Epidemiology
• Peanut
• Children in UK = 0.5% and 2.5%
• Children Aus = 3% of (12-m-old infants, positive OFC)
• Adult in UK = 0.4% to 0.7%
• German: 11% of the children were sensitized to peanuts
• EuroPrevall : sensitization rate = 0.5-7.2% in European country
• Treenut
• 0.2% to 2.2%
• Brazil nut 0.12-0.48%
• PFS of hazelnut = 4.6%

Epidemiology: Asia
• Peanut and tree nut allergy in Asia
• 0.67% in Korean infant
• 0.47-0.64% in Singaporean children
• 0.43% in Filipino children
• 0.5-1.1% in Taiwan
• The reasons for this stark difference
• Early exposure to boiled peanut
• Ethnicity
Alison Joanne Lee. Et.al. Asia Pac Allergy 2013;3:3-14

Alison Joanne Lee. Et.al. Asia Pac Allergy 2013;3:3-14

Vicki McWilliam et.al. J Allergy Clin Immunol.2018

Vicki McWilliam et.al. J Allergy Clin Immunol.2018
Summary
- Tree nut allergy is uncommon in the first year of life, likely because of limited tree
nut consumption.
- At age 6 years, tree nut allergy prevalence is similar to peanut allergy prevalence.
- More than a third of children with both peanut and egg allergy in infancy have tree
nut allergy at age 6 years.

Phenotype
• Primary nut allergy:
• Systemic ,severe reactions to nuts in patients with specific IgE
against the major storage proteins (Ara h2)
• Clinical reaction on first known ingestion of nuts
• Pollen food syndrome (PFS):
• Oral allergy syndrome
• Mild symptoms and isolated to the oropharynx.
• Anaphylaxis is uncommon.
• sIgE is directed against heat-labile proteins (PR-10 homologues)
homologous to those in pollen.
• Previously consumed the nut without symptoms prior to developing
their PFS symptoms

Risk factors for development of
nut allergy
• Eczema
• Significant risk factor for primary nut allergy
• FLG mutation
• Early-life environmental peanut exposure
• Increased risk of peanut sensitization and allergy in children who
carry an FLG mutation
• Use of eczema creams containing peanut oil
• High levels of household peanut consumption
• Risk factor for tree nut allergy:
• Peanut allergy and tree nut allergy often coexist

Risk factors for severe reaction
• Predict for severe reaction
• Previous severe reaction
• Amount of nut ingested
• BAT in children with peanut allergy
• Asthma : increase risk of fatal anaphylaxis
• Predict for mild reaction
• Sensitized only to PR-10 homologues (hazelnut or peanut)
• Not predict for severe reaction
• Hospital-based challenges are not helpful in predicting
severity of accidental reactions
• Skin prick test and serum-specific IgE if no clinical correlated

History and clinical presentation
• History of immediate reaction x 2 times → 80% probability
for predicting primary nut allergy
• IgE mediated symptoms, onset
• More severe in adults than children
• Ingestion of large quantities generally being responsible for
more severe reactions
• Tree nut
• Brazil and cashew nut → upper airway obstruction
• Peanut and cashew nut → more severe reaction than other

Skin prick test : Peanut
• It is necessary to consider the clinical context before testing
• Peanut SPT
• SPT ≥ 3 mm = positive
• SPT < 3 mm = exclude nut allergy except typical clinical history of
nut allergy (need further investigation)
• Peanut SPT ≥ 8 mm = a low sensitivity and high specificity (PPV
>95%)

Skin prick test : Tree nut
• It is necessary to consider the clinical context before testing
• Tree nut SPT
• SPT ≥ 3 mm = positive
• SPT < 3 mm = exclude nut allergy except typical clinical history of
nut allergy (need further investigation)
• Some study : SPT ≥ 8 mm for cashew, hazelnut and walnut (PPV
>95%)
• Hazelnut showed a SPT ≥ 8 mm and ≥ 17 mm with a PPV of 74% and
100%
• Generally accepted that a cut-off SPT ≥ 8 mm for a specific tree nut
is highly suggestive of clinical allergy

Peanut
Range SPT 3-16 mm
≥ 3 mm
sensitivity 80-100%
Specificity 51-76%
≥ 8 mm
Sensitivity 30-55%
Specificity 66-100%

Serum-specific total nut IgE
• Peanut
• sIgE ≥ 15 KU/L is highly specific with a PPV in excess of 90%
• Tree nut
• Hazelnut sIgE ≥ 15 KU/L has a PPV of 57%, sIgE < 0.35 KU/L has a
NPV of 95%
• Walnut sIgE ≥ 18.5 KU/l has a PPV of 99%, specificity 98%
• Tree nuts’ sIgE cut-offs are limited although it has been suggested
that a cut-off ≥ 15 KU/L

Range SPT 0.35-15 kU/L
≥ 0.35 kU/L
sensitivity 75-100%
Specificity 29-58%
≥ 15.0 kU/L
Sensitivity 28-73%
Specificity 92-100%
Peanut

Specific IgE or SPT to
non-index nuts
• Children with one nut allergy have a significantly increased
risk of allergy to other nuts
• Performing SPT or sIgE to the other nuts in this situation
may be helpful.
• Wheal diameter is large (>8 mm) or sIgE is high → allergy is likely
• SPT is negative or sIgE < 0.35 KU/L→allergy to those nuts is unlikely
• SPT wheals 3–7 mm are indeterminant as patients could be tolerant
or allergic

Oral Food Challenge
• Oral food challenges to nuts → definitive diagnosis
• Appropriate setting with access to resuscitation
equipment

CRD
• There are few data comparing performance of
peanut SPT to slgE peanut components
• Ara h 2 is the major peanut allergen, and sIgE
directed against this shows better discrimination
than total peanut IgE

Peanut Allergy
Jörg Kleine-Tebbe.EAACI Molecular Allergology User´s Guide.2016
Skin sensitization in children
Cross reactivity with Pru P3

PPV
sIgE Ara h2
NPV
sIgE Ara h2

van Erp et al. Curr Treat Options Allergy (2016) 3:169–180

Tree nut allergen
• Major allergen in peanut and legumes = Seed
storage protein
• Vicilins (7s globulin) : Ara h1
• 2S albumin : Ara h2,6 Ber e1, Ana o3
• Legumins (11s globulin) : Ara h3
J. M. Smeekens et.al. Clin Exp Allergy. 2018;48:762–772.

Vicilin protein
Walnut (Jug r 2) VS Pecan (Car I 2)
Caschew (Ana o 1) VS Pitachio (Pis v3)

2S albumin allergen

Legumin allergen

High cross reactivity between
tree nut
Anacardiacea family
Juglandacea family
Cashew Pistachio
Walnut Pecan
Vicilin protein
2S albumin allergen
Legumin allergen

Scott H. Sicherer. Allergy Clin Immunol 2001;108:881-90.

https://theallergygroup.com/Blog/ArticleID/99/Oral-Allergy-Syndrome-Pollen-Food-Cross-reactivity

Patient with high risk PN allergy (Severe AD)

Patient with history of immediate reaction of peanut consumption

Accidental finding PN sensitization

AnaphylaxisMild OAS
OAS or additional
cough and nausea

Non-medication
• Dietary management
• All patients and their families/carers require clear
information on nut avoidance
• Food labelling
• Ingredients list
• ‘may contain’ or ‘not suitable for’
• Precautionary allergen labelling (PAL)

Non-medication
• Eating out
• Legislation requires restaurants, and cafes to provide
clear information about nuts in non-packaged foods.
• High risks = Asian restaurants, ice cream shops, bakeries
• Single vs. all nut exclusion
• Patients with peanut allergy to also avoid tree nuts
• simplify the message and improve avoidance while
eating in schools and restaurants

Medical management
• Provision of emergency medication
• All patients should be supplied with oral antihistamines
• Long-acting antihistamines with rapid onset of action,
e.g. cetirizine
• AAI provision and training
• All at-risk patients will require adrenaline to treat an
episode of anaphylaxis
• Encouraging patients to carry AAI at all times is an
essential part of training.
• The provision of written emergency action plans is
essential

OIT
• Objectives
• To evaluate the efficacy and safety of AR101 in children and adults
with peanut allergy.
• Population
• In a phase 3 trial, we screened participants 4 to 55 years of age with
peanut allergy
• Intervention
• 3:1 ratio, to receive AR101
• Escalating dose, maintenance dose 300 mg/day for 24 weeks
• Total duration about 52 weeks
The PALISADE Group of Clinical Investigators.N Engl J Med 2018;379:1991-2001.

OIT
Outcome AR101 group Placebo group P value
OFC pass at least
600 mg of peanut
(age 4-17)
67.2% 4% < 0.01
(95CI = 53-73.3)
Moderate adverse
events
25% 59% < 0.01
Severe adverse
events
5% 11% < 0.01
No statistical significant between 2 group: sIgE for PN, IgG4 for PN, SPT size
Summary
- AR101 was an immunomodulatory treatment that resulted in desensitization
in children and adolescents who were highly allergic to peanut.
- No significant effect was found in participants 18 to 55 years of age.

EPIT
• Objectives
• To determine the optimal dose, adverse events (AEs), and
efficacy of a peanut patch for peanut allergy treatment.
• Population
• Peanut-allergic patients (6-55 years) from 22 centers
• Intervention
• Randomly assigned patients (1:1:1:1) received an EPIT
containing
• 50 μg (n = 53)
• 100 μg (n = 56)
• 250 μg (n = 56)
• placebo patch (n = 56)
• Following daily patch application for 12 months
Hugh A. Sampson. JAMA. 2017;318(18):1798-1809

250mcg100mcg50mcg

IgE 6-55 Y
IgE 6-11 Y
IgE 12-55 Y
IgG4 6-55 Y
IgG4 6-11 Y
IgG4 11-55 Y

Prognosis
• PFS with respect to nuts : No data
• Peanut allergy
• In children under 2 years : 21% outgrew their allergy
• 1 study: PA at 1 year of age by OFC and by 4 years of age,
22% had resolved PA
• Tree nut allergy
• 1 study on tree nut allergy : approximately 9% of
children outgrew their tree nut allergy

Rachel L. Peters et.al. Allergy Clin Immunol 2015;135:1257-66.
In a population-based cohort we report that
22% of challenge-confirmed peanut allergy
resolves by 4 years

SPT PN
- Decreasing wheal size predicted tolerance
- Increasing wheal size was associated with
persistence
PN SPT
sIgE PN

Summary
- SPT and sIgE 95% PPVs will be useful in reducing the need for unnecessary OFCs in children
with a high risk of persistent peanut allergy,
- 50% NPVs will indicate which children should be considered for OFCs for tolerance
development.
At 1 years of age: SPT ≥ 13 mm, sIgE PN ≥ 5 kUA/L are high PPV (95%)
At 4 years of age: SPT ≥ 8 mm, sIgE PN ≥ 2.1 kUA/L are high PPV (95%)
At 4 years of age: SPT less than 3 mm high NPV (90%)

• Objectives
• To investigate roles of component-resolved diagnostic (CRD) to
differentiate peanut allergy and peanut tolerance in the Asian
population
• Population
• CRD analysis in 40 participants with peanut sensitization
• Intervention
• 19 peanut allergy
• 21 peanut tolerance
• 40 performing CRD analysis: rAra h 1, rAra h 2, rArah 3, rAra h 9,
nGly m 5, nGly m 6, rBet v 1, rBet v 2, rPhl p 12, and CCD
Suratannon et.al. Pediatr Allergy Immunol 2013: 24: 665–670.

Conclusion
- rAra h 2 is confirmed to be the most important allergen and a severity marker.
- rAra h 9 should be included in peanut panel testing when rAra h 2 sIgE was negative.
- Measurement of IgE to CCD in subjects with positive sIgE to peanut but having negative
results to rAra h 2 and rAra h 9 sIgE further helps to discriminate between peanut-
tolerant and peanut-allergic subjects.

Tree nut
• Tree nut allergy had also long been considered as a lifelong
condition
• Fleischer and colleagues
• Patients who had both prior clinical reactivity and evidence of TN-
IgE
• OFC prove: 8.9% acquired oral tolerance (95% CI, 4–16%)
• 4/9 were outgrown to cashew, 3/9 to pecan, and 2/9 to walnut
A. M. Byrne. et.al.Clinical & Experimental Allergy, 40, 1303–1311

Tree nut
• Predictors of tree nut allergy resolution
• Low prevalence of AD (P = 0.009)
• Outgrown peanut allergy (in patient multiple nut allergy)
(P=0.0001)
• Outgrown other tree nut allergy (P=0.0001)
• Outgrown other food allergy (P = 0.03)
• No significant with other allergic diseases
A. M. Byrne. et.al.Clinical & Experimental Allergy, 40, 1303–1311

LEAP
• Objective
• We evaluated strategies of peanut consumption and avoidance to
determine which strategy is most effective in preventing the
development of peanut allergy in infants at high risk for the allergy
• Population
• High risk group: infants 4 months-11 months of age , severe
eczema, egg allergy, or both
• Intervention
• SPT : positive, negative group
• Avoidance and consumption group (6g/week)
Du Toit et.al. N Engl J Med 2015;372:803-13.

Intention to treat
Per protocol analysis
Worse case imputation

Summary
Early oral introduction of peanuts could prevent allergy in high-risk, sensitized infants
and in nonsensitized infants

EAT
• Objective
• The early introduction of allergenic foods in the diet of breast-fed
infants would protect against the development of food allergy
(between 1 year and 3 years of age)
• Population
• Singleton infants who were 3 months of age and exclusively breast-
fed N = 1303
• Intervention
• RCT 2 group : early consumption (age < 6 m), late consumption (age
> 6 m)
• 6 food (PN, Cook egg, CM, Sesame, white fish, wheat)
Michael R. Perkin et.al. N Engl J Med 2016;374:1733-43.

Early peanut consumption also resulted in a rate of peanut allergy that
was 10 times lower than that among the participants in the standard-
introduction group (2.5% vs. 0.2%)

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