Peanut allergy

Peanut Allergy
• Topic Review
• May 8th, 2020
• Rapisa Nantanee, M.D.
• Pediatric Allergy and Immunology Unit
• King Chulalongkorn Memorial Hospital
This Photo by Unknown Author is licensed under CC BY-NC

Outline
• Introduction
• Prevalence
• Genetics of Peanut Allergy
• Environmental Risk Factors for
Food Allergy
• Peanut Allergens
• Effects of Processing on the
Allergenicity
• Clinical Manifestations
• Environmental Food Exposure
• Diagnosis
• Cross Reactivity
• Natural History
• Treatment
• Prevention

Introduction
• Peanut (Arachis hypogaea)
• Geocarpic fruiting habit
• It flowers aboveground but produces its seed‐containing pods
underground.
• A member of the legume family (Fabaceae)
• Soybean (Glycine max)
• Lupine (Lupinus angustifolius, Lupinus albus)
• Lentil (Lens culinaris)
• Pea (Pisum sativum)
• Green bean (Phaseolus vulgaris)
P. Ozias-Akins, H. Breiteneder. Allergy. 2019;74:888–898.
B. Cabanillas, et al. Mol. Nutr. Food Res. 2018, 62, 1700446.

Soybean
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This Photo by Unknown Author is licensed under CC BY-NC-ND
Lupini beans
Lentil
Pea
This Photo by Unknown Author is licensed under CC BY-NC-ND
Green bean

Black turtle
beans
Mung beans
This Photo by Unknown Author is licensed under CC BY-SA-NC
Kidney beans

Prevalence: US Children
• A population-based, cross-
sectional survey was administered
between June 2009 and February
2010 to a representative sample
of US households with children.
• 38 480 children
• A mean age of 8.5 years (95%
confidence interval [CI]: 8.5 – 8.6)
• Frequency 2 % (95% CI: 1.8 –
2.2)

Prevalence: US Adults
• Surveys were completed by 40 443 adults (mean [SD] age, 46.6
[20.2] years).
• The 5 most common convincing food allergies reported among
adults were
• shellfish (2.9%; 95%CI, 2.7%-3.1%)
• peanut (1.8%; 95%CI, 1.7%-1.9%)
• milk (1.9%; 95%CI, 1.8%-2.1%), tree nut (1.2%; 95%CI, 1.1%-1.3%),
and fin fish (0.9%; 95%CI, 0.8%-1.0%).
RS. Gupta, et al. JAMA Network Open. 2019;2(1):e185630.

Prevalence: Europe
• Age-stratified pooled
prevalence of peanut allergy
(PA) in studies published in
Europe between January
2000 and September 2012.
• The overall lifetime
prevalence was 1.6% (95%
CI 1.2–1.9) for FC or history
of peanut allergy.
B. I. Nwaru, et al. on behalf of the EAACI Food Allergy and
Anaphylaxis Guidelines Group. Allergy 2014; 69: 992–1007.

Prevalence: Europe
B. I. Nwaru, et al. on behalf of the EAACI Food Allergy and
Anaphylaxis Guidelines Group. Allergy 2014; 69: 992–1007.

Prevalence: Singapore and Philippines
LP. Shek, et al. J Allergy Clin Immunol 2010;126:324-31.

Genetics of Peanut Allergy
• There is a strong genetic contribution to peanut allergy with 64%
concordance in monozygotic twins.
• A Canadian genome-wide association study (GWAS) established
C11orf30 (chromosome 11 open reading frame) as a risk locus for both
peanut and food allergy.
• Code for histone-related proteins active in epigenetic regulation of gene expression
• Suggesting that epigenetic regulation plays a role in development of food allergy.
• A German GWAS identified five loci at genome-wide significance, the
clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene
cluster at 5q31.1, the filaggrin gene, the C11orf30/LRRC32 locus, and the
human leukocyte antigen (HLA) region.
• The HLA locus appears to be peanut allergy–specific whereas the other four loci
increase the risk for any food allergy.
A. Nowak-Węgrzyn, et al. Middleton 9th ed. Chapter 79.

Environmental Risk Factors for Food
Allergy
• The rapid rate of increasing prevalence suggests that
environmental factors play a more important role, likely by
affecting the expression of genetic susceptibility.
• The hygiene hypothesis
• suggests that the lack of early life exposures to infectious agents (e.g.,
bacteria, parasites) leads to faulty programming of tolerogenic
mechanisms, increasing the host’s susceptibility to allergic diseases.
• Additional potential environmental risk factors for food allergy
• cesarean delivery, dietary factors, timing of the allergenic food
introduction into the infant diet, and integrity of the skin barrier

Peanut Allergens
• 16 peanut allergens are officially recognized by the
WHO/IUIS Allergen Nomenclature Sub‐Committee.
• According to their protein architecture, peanut allergens can
be classified into 7 groups.

GA. Stewart, C. Robinson. Middleton 9th ed. Chapter 26.
Major
Allergens
Ara h 6 has 53% sequence identity to Ara h 2,
compared with Ara h 7 sequence identity to Ara h 2
of 44%.

Peanut
Allergens
The prolamin
superfamily
The cupin
superfamily
The pathogenesis-related
(PR) proteins family
The profilins family
2S albumins
Non-specific Lipid
transfer proteins
(ns-LTP)
- Ara h 2, Ara h 6, Ara h 7
- High resistance to heat and
digestive enzymes
- High association with severe
anaphylactic reactions
Ara h 9, Ara h 16, Ara h 17
- Ara h 3
- Ara h 8 is a PR‐10 protein, a homologue to
the major birch pollen allergen Bet v 1
- Low stability during roasting and no stability in
gastric digestion
- Ara h 5 is a pan-allergen
- Profilins are small cytoplasmic proteins and are
present in all eukaryotic cells.
B. Cabanillas, et al. Mol. Nutr. Food Res. 2018, 62, 1700446.
th
11S globulin
7S globulin
- Ara h 1
- Interact with lipid components
- conferring resistance to digestive
enzymes and interacting with dendritic
cells in a way that can favor the
generation of Th2 responses.
Oleosins
- Ara h 10, Ara h 11, Ara h
14, Ara h 15
- Peanut oil proteins
- Associated with severe
allergic reactions
- Dry roasting increases
oleosin allergenicity
Defensins
- Ara h 12 and Ara h 13
- Plant defense against
pathogens
- Severe peanut allergy

Effects of Processing on the Allergenicity
ENC. Mills. Middleton 9th ed. Chapter 31.

Effects of Processing on the Allergenicity
ENC. Mills. Middleton 9th ed. Chapter 31.
Highly refined
peanut oil was
found to be safe in
60 peanut-allergic
individuals,
whereas pressed
(or extruded) oils
were found to
retain some of
their allergenicity.

Clinical Manifestations
A. Deschildre, et al. Clinical & Experimental
Allergy, 2016 (4) 610-620.

Food‐induced
anaphylaxis
deaths
G. Pouessel, et al. Clin Exp Allergy. 2018;48:1584–1593.
The most frequent
food allergens
involved in lethal
anaphylaxis at any
age are peanut and
tree nuts,
accounting for
55%‐87% of deaths

Environmental Food Exposure:
Important Terms
• Cross-contact occurs when one type of food comes into
contact with another type of food, resulting in the mixture of
proteins.
• An allergen is inadvertently transferred to
a food/meal that is thought to not contain
that specific allergen.
• Precautionary allergen labeling (PAL)
• Environmental food allergen exposure
• refers to residual food proteins that can be measured on floors,
furniture, and surfaces, or in the air.
• typically not thought to result in a classic ingestion-mediated food
allergy reaction, but instead can play a role during cutaneous exposure
to food allergens.
WJ. Sheehan, et al. J Allergy Clin Immunol Pract 2018;6:1825-32.
Cross-contamination refers to the
process of microorganisms such as
bacteria or viruses being unintentionally
transferred into foods during the
preparation or storage.

Evaluation of the Presence of Food
Allergens in Different Scenarios
• Peanut allergen on hands after eating peanut
• Use soaps rather than alcohol-based sanitizer to remove food allergens from
hands
• Food allergens in the home kitchen
• Using commercial cleaning agents containing bleach rather than dishwasher
liquid alone to remove peanut from table surfaces.
• Food allergens in food challenge unit
• peanut protein could be detected on bed pillows and various surfaces within
the clinical area (children’s play table, toy stand, TV stand) and within the
kitchen preparation area (taps, table tops, microwave)
• The detected levels would be unlikely to be high enough for clinical reactions
via the oral route.

• Food allergens in household dust
• A wide range of food allergens have been detected in household dust,
including peanut, egg, cow’s milk, and fish.
• Peanut levels in bedroom dust are strongly correlated with
household peanut consumption.
• Hypothesis that environmental peanut exposure may increase the
risk of developing peanut allergy in young infants.

• Food allergens in school dust
• Whole peanut protein was detectable in 100% of vacuumed floor dust
samples from elementary schools in the United States, with similar
levels in both classrooms and cafeterias.
• Ara h 1 was not widely detectable by monoclonal ELISA testing of
surfaces wipes collected from elementary schools.
• Airborne food allergens
• Aerosolization of food proteins can occur during the cooking or
manipulation of certain foods.
• There was detectable airborne peanut protein; however, this was only
for a brief time and only directly above the peanuts while deshelling.

• Food allergens in airplanes
• General recommendation that food-allergic individuals clean tray tables
and seat cushions using bleach or alcohol-based sanitizing wipes
before the start of a flight.
• Food allergens in restaurants
• Silent danger of cross-contact in food preparation
• In a study of food-allergic individuals who reported having a reaction at
a restaurant, 22% of cases were reported to be the result of cross-
contact from shared cooking or serving supplies.

• Food allergens in manufacturing
• Food manufacturers also frequently apply voluntary PALs (eg, “may
contain”) to packaged foods made with use of shared equipment or
facilities.
• Because worldwide regulatory agencies have not yet accepted the
concept of thresholds, food manufacturers often use effective
preventive allergen controls, but still apply PAL to their packaged foods.
• Thus, some but certainly not all foods with PALs are safe for
allergic consumers.

Diagnosis of IgE-mediated peanut
allergy
• Skin prick testing
• Peanut sIgE (Whole peanut)
• sIgE to peanut components (component-resolved diagnosis)
• Oral food challenge
• Basophil activation test
• Mast cell activation test
• Histamine release assays
• Other emerging diagnostic tests
• Other methods of provocation
Krogulska, RA. Wood. Pediatr Allergy Immunol. 2020;00:1–12.
JJ. Koplin, et al. J Allergy Clin Immunol Pract 2019;7:375-80.

Definitions
• Sensitivity: the proportion of true positives (peanut-allergic
individuals) correctly identified as peanut allergic by the
diagnostic test.
• Specificity: the proportion of true negatives (peanut-tolerant
individuals) correctly identified as peanut tolerant by the
diagnostic test.
• Positive predictive value (PPV): the proportion of test-positive
patients who are truly peanut allergic.
• Negative predictive value: the proportion of test-negative
patients who are truly peanut tolerant.
dependent on the underlying prevalence of disease

Skin prick testing
• A key advantage of SPT is that results are immediately available.
• High sensitivity 94.7% (95% CI, 87.9-97.8)
• Low specificity 61.0% (95% CI, 46.6-73.6)
• An SPT wheal size of 8 mm had a 95% PPV for peanut allergy
• A specificity of 98% (95% CI, 95-99) and a sensitivity of 54% (95% CI, 46-62).
• A decreasing wheal size between age 1 and 4 years predicted
development of tolerance to peanut.
• There was significant variability between individuals.
• A useful tool to exclude peanut allergy in an individual with an
unclear clinical history if the test result is negative.
• Various factors have also been shown to influence SPT wheal size,
including choice of SPT device and reagents, technique, and even
site of SPT.

Peanut sIgE (Whole peanut)
• High sensitivity 96.3% (95% CI, 91.6-98.4)
• Low specificity 59.3% (95% CI, 45.4-72.0) (mixed cutoffs)
• Decreasing sIgE levels to peanut are associated with resolution of
peanut allergy.
• 95% PPV for sIgE testing, with varying results
• In the HealthNuts study, sIgE levels above 34 kUA/L had a 95% PPV for
peanut allergy at age 1 year, whereas at age 4 years the corresponding 95%
PPV was 2.1 kUA/L.
• Other studies have suggested a threshold of 15 kUA/L for children with a
median age of 3.8 years.
• Measuring sIgE levels has advantages over SPT in some settings
because
• It can be performed even in patients with severe eczema who may not have a
patch of clear skin for SPT, and does not require patients to avoid
antihistamines before testing.

J.A. Bird, et al. J Allergy Clin Immunol Pract 2020;8:75-90.

sIgE to peanut components
(component-resolved diagnosis)
• Peanut components that have been tested in clinical studies
include Ara h 1, 2, 3, 6, 8, and 9.
• Ara h 2 provided the best combination of diagnostic accuracy
measures, and was mainly superior to SPT and sIgE for
diagnosing peanut allergy in case of a positive test result.
• Increasing levels of component sIgE to Ara h 2 are also associated with
an increasing likelihood of true peanut allergy.
• Ara h 6 might have a higher diagnostic accuracy for peanut
allergy compared with Ara h 2.
• But comparison between studies was difficult due to varied cutoff
values, and concluded that more research is required.

A. Krogulska, RA. Wood. Pediatr Allergy Immunol. 2020;00:1–12.

Oral food challenge
• Double-blind placebo-controlled oral food challenge (DBPCFC)
remains the gold standard of diagnosing FA.
• Although OFCs have great diagnostic value, they carry significant
risk.
• Indication
• Patients without any clear clinical history or laboratory evidence that
points toward PNA
• Introduction of peanuts in patients who are sensitized but have not eaten
peanuts
• In children with PNA after a period of avoidance, to evaluate the possibility of
oral tolerance acquisition
• Infants following the new recommendations based on the results of the LEAP
study
• Research

Risk factors for severe OFC reactions
• Several studies suggest that the level of sIgE can sometimes
correlate with the severity of a PNA reaction, although others show
opposite results.
• If a patient is found to be sensitized only to PR-10 homologues and has a
clinical history of only mild reactions, it may be reasonable to assume that the
risk of a future severe reaction is low and PFS is possible.
• sIgE/total IgE ratio is more accurate than sIgE alone in predicting
outcomes of challenges performed to confirm PN tolerance.
• BAT CD63 ratio, together with the history of exercise-induced
asthma, and FEV1/FVC ratio at the time of DBPCFC may be used
to predict severity of reaction during peanut OFC.

OFC: Doses, intervals, new protocols
• The initial and total dose of the challenge should be adjusted
according to the clinical history and age.
• The findings concerning the relationship between threshold
dose and reaction severity are varied.
• The higher doses of PN do not increase the severity of reactions.
• Low individual reaction thresholds do not necessarily correlate with
severe reactions.

OFC: Doses, intervals, new protocols
• In the PAT (Peanut Allergen Threshold) study, a novel single-
dose protocol was used to assess the ED05 (the dose that
elicits a reaction in 5% of allergic subjects)
• 1.5 mg of peanut protein (or 6 mg of whole peanut or approximately
1/100th of a peanut kernel)
• Does not replace current clinical OFC.
• Could be performed before starting a progressive clinical OFC to
identify the most sensitive patients and reduce any risks
associated with the use of higher doses
• The protocol was very acceptable to families, clinically very safe, easier
to perform than routine diagnostic OFCs and it improved food allergy-
related quality of life.

A. Krogulska, RA. Wood. Pediatr
Allergy Immunol. 2020;00:1–12.

Basophil activation test
• The key strength of the BAT is the ability to accurately differentiate
between allergic and tolerant patients and have a superior
specificity and comparable sensitivity compared with other
diagnostic tests.
• Being able to be performed even in children with extensive eczema who have
had recent antihistamine medication and a high safety profile.
• High sensitivity (83% to 92%) and specificity (77% to 100%)
• The most accurate and cost-effective analysis was found to be when
an equivocal peanut SPT or Ara h 2-sIgE was followed by BAT.
• A positive BAT result would remove the need for an OFC.
• However, a patient with a negative BAT result or nonresponder
basophils (basophils that do not respond to IgE-mediated stimulants)
would still require the criterion standard OFC test to confirm or refute
the diagnosis.

Mast cell activation test
• The function of the individual’s allergen sIgE antibodies’ ability
to elicit mast cell degranulation
• Once mast cell cultures are established, they are sensitized
passively with individual patient sera, incubated with allergen in
vitro, and assessed for mast cell activation by flow cytometry.
• A definite advantage of the MAT over the BAT is
• The use of stored plasma rather than fresh whole blood
• High specificity
• Provided definitive results for all individuals with nonresponding
basophils

Histamine release assays
• Measures the amount of histamine released from activated
basophils
• Whole blood (collected < 24 hours from sampling) is incubated with
peanut extract or anti-IgE, released histamine binds to a solid glass
fiber phase, and unbound blood is removed with repeated washing.
Trapped histamine is obtained from the solid phase by increasing pH
and quantified flurometrically.
• A modified passive HR assay using an individual’s serum has also
been developed to overcome the need for fresh blood.
• The BAT displayed a significantly higher CD sensitivity (a
measure of basophil allergen sensitivity) compared with HR
assay and passive HR assay (80%, 23%, 11%); however,
excluding inconclusive tests, diagnostic accuracy was
comparable.

Other emerging diagnostic tests
• IgE-binding epitopes
• Peptide microarrays
• Sequential IgE-binding epitopes may play a role of biomarkers for
characterizing numerous phenotypes of FA.
• A higher ratio of sequential epitopes than conformational epitopes predicted a
more persistent and severe course of FA.
• A basophil-mediated microarray immunoassay was recently developed.
• The printed spots of protein or peptide-containing allergenic epitopes were not
detected with patient's serum IgE but with human basophils passively sensitized with
patient's serum.
• Peanut-stimulated T-cell cytokine production and mRNA expression
profiles
• Predictive models
Krogulska, RA. Wood. Pediatr Allergy Immunol. 2020;00:1–12.

Other methods of provocation
• The peanut conjunctival allergen provocation test (CAPT)
• a safe in vivo alternative to OFC
• The sensitivity and specificity of the CPT were 0.96 and 0.83.
• Although not sufficient to replace other diagnostic methods, both CRD
and CAPT may improve diagnostic accuracy.

Cross Reactivity
• Structural homology among allergens underlies immunologic
and clinical cross-reactivity.
• More than 70% identity in the primary sequence is considered
necessary for clinical cross-reactivity.
• Modulated by additional factors, including protein solubility and
digestibility, concentration and affinity of the specific IgE antibody, and
the dose and route of allergen exposure.
• 5% amomg peanuts and other legumes

Of the 147 children with peanut allergy at age 6
years, 45% also had 1 or more tree nut allergies.
V. McWilliam, et al. J Allergy Clin Immunol 2019;143:644-50.

V. McWilliam, et al. J Allergy Clin Immunol 2019;143:644-50.
Of those with peanut allergy
only at age 1 year, 27% had
tree nut allergy at age 6 years.

Brian Schroer, Jaclyn Bjelac. Immunol Allergy Clin N Am 39 (2019) 495–506.

Natural History
• Peanut allergy has a worse prognosis compared with milk and egg
allergy because it is generally less likely to be outgrown.
• In the prospective HealthNuts study, peanut allergy resolved by age
4 years in 22% of children with challenge-confirmed peanut allergy at
age 1 year.
• Although most peanut tolerance develops in early childhood, cases
of resolution in adulthood have been reported.
• Symptomatic peanut allergy has been demonstrated to recur after
passing an open challenge.
• This has been seen especially in sensitized patients who do not introduce
peanut into their diets after a negative peanut challenge.
J. Savage, et al. J Allergy Clin Immunol Pract 2016;4:196-203.

J. Savage, et al. J Allergy Clin Immunol Pract 2016;4:196-203.

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