ArticlePDF AvailableLiterature Review

Recent advances in the management of nut allergy

January 2021
World Allergy Organization Journal 14(1):100491

DOI:10.1016/j.waojou.2020.100491

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Authors:

Suzana Radulovic

Guy's and St Thomas' NHS Foundation Trust

Helen Brough

Guy's and St Thomas' NHS Foundation Trust

Jean-Christoph Caubet

University of Geneva

Peanut/tree nut allergy is common and has been associated with particularly severe reactions. Epidemiological data have shown that the prevalence ranges between 0.05% and 4.9% for tree nut and between 0.5% and 3% for peanut. These large variations can be explained by differences in the age of included patients and the geographical region. In addition, the food consumption modality (ie, raw versus roasted) plays a major role, as heat treatment has the capacity to modify the allergenicity of nuts and legumes. Nut allergies tend to persist into adulthood and consequently have a high impact on quality of life. Recently, it has been demonstrated that a significant proportion of nut allergic patients are able to tolerate other nuts. As opposed to the avoidance of all nuts, this approach is currently proposed in several tertiary allergy centers. However, diagnosis of nut allergy is particularly difficult due to co-sensitization leading to high rate of false positive skin prick tests and/or specific IgE to whole allergen extracts. The use of component resolved diagnosis leads to major improvement of diagnosis, particularly to distinguish between primary and secondary nut allergies. The basophil activation test has been suggested to be useful but is still used mainly as a research tool. Thus, diagnosis remains mainly based on the oral food challenge, which is considered as the gold standard. Regarding treatment, avoidance remains the cornerstone of management of nut allergy. Oral immunotherapy is increasingly proposed as an alternative management strategy.

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Open Access

Recent advances in the management of nut

allergy

Elise Midun

*, Suzana Radulovic

, Helen Brough

and Jean-Christoph Caubet

ABSTRACT

Peanut/tree nut allergy is common and has been associated with particularly severe reactions.

Epidemiological data have shown that the prevalence ranges between 0.05% and 4.9% for tree

nut and between 0.5% and 3% for peanut. These large variations can be explained by differences

in the age of included patients and the geographical region. In addition, the food consumption

modality (ie, raw versus roasted) plays a major role, as heat treatment has the capacity to modify

the allergenicity of nuts and legumes. Nut allergies tend to persist into adulthood and conse-

quently have a high impact on quality of life.

Recently, it has been demonstrated that a signiﬁcant proportion of nut allergic patients are able to

tolerate other nuts. As opposed to the avoidance of all nuts, this approach is currently proposed in

several tertiary allergy centers. However, diagnosis of nut allergy is particularly difﬁcult due to co-

sensitization leading to high rate of false positive skin prick tests and/or speciﬁc IgE to whole

allergen extracts. The use of component resolved diagnosis leads to major improvement of

diagnosis, particularly to distinguish between primary and secondary nut allergies. The basophil

activation test has been suggested to be useful but is still used mainly as a research tool. Thus,

diagnosis remains mainly based on the oral food challenge, which is considered as the gold

standard.

Regarding treatment, avoidance remains the cornerstone of management of nut allergy. Oral

immunotherapy is increasingly proposed as an alternative management strategy.

Keywords: Food allergy, Tree nut, Peanut, Cross reactivity, Oral immunotherapy

INTRODUCTION

Peanut and Tree nut (TN) allergies are one of the

most common food allergies worldwide and

constitute a major public health problem. The

estimated prevalence of peanut/tree nut allergies

is approximatively 2%.

1–4

There is a large variation

in prevalence reported in different countries, ie,

from 0.05% to 4.9% for tree nut and between

0.5% and 3% for peanut.

1,3,5–7

Peanut allergy is

the most common nut allergy. The allergy

prevalence for each tree nut seems to vary in

different parts of the world.

1,7–10

Indeed,

hazelnut allergy is the most frequent tree nut

allergy in continental Europe; Brazil nut, walnut

and almond are most commonly reported in the

United Kingdom;

1,11

and walnut and cashew nut

allergy are the most common tree nut allergies in

the United States.

1,12

These differences are

Pediatric Allergy Unit, University Hospitals of Geneva and University of

Geneva, Rue Willy Donzé 6, 1205 Geneva, Switzerland, University Lyon 1

Claude Bernard, 43 Boulevard Du 11-Novembre-1918, 69100, Villeurbanne,

France

*Corresponding author: elisemidun@live.fr

Full list of author information is available at the end of the article

http://doi.org/10.1016/j.waojou.2020.100491

Received 21 May 2020; Received in revised from 2 November 2020;

Accepted 3 November 2020

Online publication date xxx

World Allergy Organi zation. This is an open access article under the CC BY-

NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Midun et al. World Allergy Organization Journal (2021) 14:100491

http://doi.org/10.1016/j.waojou.2020.100491

mainly due to the variation of nuts consumed in

different countries. However, prevalence

variations have also been reported within the

same country, highlighting the possible inﬂuence

of environmental factors such as pollen

exposure.

1,4

An important aspect of nut allergy is the risk of

potentially life-threatening allergic reactions.

Indeed, nut allergies have been associated with

severe allergic reactions more commonly than the

majority of other foods. Recent studies reported

that peanut/TN allergies account for 70–90% of

fatalities from food-induced anaphylaxis, with TN

alone accounting for 18–40%.

Peanut and TN

allergies also tend to persist, and the acquisition

of natural tolerance to peanut/TN occurs in only

9%–20% of peanut/TN allergic patients.

Despite

years of research and clinical efforts, strict

avoidance of the incriminated nut (peanut/TN)

remains the cornerstone of management. Thus,

quality of life (QoL) is reduced with increasing

stress and anxiety due to the need for constant

vigilance.

14,15

Although other treatment options, such as oral

immunotherapy, have been largely investigated

for peanut and TN allergic patients, their use

currently remains limited.

Management of patients with peanut/TN allergy

is often quite complex. The distinction between

cross-sensitization and clinically relevant cross-

reactivity between TN and also peanut can be

difﬁcult and often requires multiple investigations

and oral food challenges (OFC). While avoidance

of all nuts has been the rule for a long time in

patients allergic to one nut, the possible

Proportion of co-

sensitization

Proportion of self-

reported co-allergy

Proportion of co-allergy

conﬁrmed by OFC

Sicherer et al.

34%

Maloney et al.

86% 34%

Anagnostou et al.

80%

Cousin et al.

87,1% 43,2%

Ball et al.

23,4% of peanut-allergic

patients are sensitized to

nuts.

25,4% of patients allergic

to nuts are sensitized to

peanuts or other nuts.

32% of peanut-allergic

patients are sensitized to

nuts.

38% patients allergic to

nuts are allergic to

peanuts or other nuts.

Yang et al.

51% of patients allergic to

nuts are sensitized to

peanut

73% of patients allergic to

peanut are sensitized to

nuts

Clark et al.

At 2 yr of age: 19% of

children were

multi-sensitized

At 5-14 yr: 86% were multi

sensitized

2% of children were

multi allergic

At 14yr: 47% of

children were

multi-allergic

Elizur et al.

60,6 %to 96,7% <30%

Couch et al.

12%

Brough et al.

60,7%

Table 1. OFC: oral food challenge, yr: year.

2Midun et al. World Allergy Organization Journal (2021) 14:100491

http://doi.org/10.1016/j.waojou.2020.100491

introduction of other nuts has recently been

investigated in several studies.

17–20

For the purpose of this review, we will discuss

these different aspects constituting advances in

the management of nut allergies.

Proportion of patients reacting to multiple nuts

Prevalence of co-sensitization and co-allergy

Co-existent allergy peanut and TN have been

described for many years. Initially, in the 90s,

Sicherer et al reported that 34% of patients allergic

to peanut or 1 TN may present with multiple nut

allergy.

However, further studies reported a

large variation in the proportion of patients

reacting to multiple nuts, ranging from 12% to

96.7%.

4,15,21–28

These data have been

summarized in Table 1.

The inﬂuence of pollen allergy, the population

studied as well as its ethnicity are all confounding

factors that might inﬂuence the results. In addition,

these differences can be explained by differences

in the methodology of the studies.

Thus, studies that reported on speciﬁc IgE found

that the co-sensitization rate among TN and pea-

nut ranged between 60.6% and 96.7%.

24–26,28–30

When a positive clinical history is required to

diagnose nut allergy, but without a conﬁrmatory

OFC, the proportion of patients with multiple nut

allergy is lower than expected, ranging between

23% and 68%

4,21–25

(Table 1).

Studies including OFCs to prove co-existent

peanut/TN allergy, considered as the gold stan-

dard, report a rate co-existent allergy of 12%–

38.8% and conﬁrmed initial data by

Sicherer

4,15,26,27

(Table 1). However, a recent

prospective multicenter study in Europe (Pronuts

study) based on 122 patients that underwent

sequential OFC to determine allergy versus

tolerance, showed a higher rate of co-existent

peanut/TN or sesame seed allergy at 60.7%.

These results could be explained by the fact that

the Pronuts study was prospective as opposed to

retrospective in the previous studies,

27,31

assessed all 9 TNs (compared to other studies

testing less TNs),

27,30

and included sesame seed

which belongs to the Pedaliaceae (seeds) family.

The NutCracker study which was also a

prospective study including OFCs, reported a

lower prevalence of multiple nut allergy below

30%,

however, this study (based on a cohort of

83 children with TN allergy in Israel) included

only OFCs to a subset of TN (walnut, pecan,

cashew, pistachio, hazelnut, and almond), which

could potentially underestimate the rate of co-

existent allergy.

Couch et al in a recent

retrospective study, found similar results; 67

patients with a history of TN allergy underwent

an OFC to another TN to which they were

sensitized, but not exposed to before.

Interestingly, only 14% of the included patients

had a positive OFC to another TN. However, this

study was retrospective and patients in this study

had relatively low levels of speciﬁc IgE (90% of

these patients had a sIgE <2 kU/L and at least

half had a level <0.35 kU/L); thus, these patients

were probably selected for OFC based on lower

IgE tests to conﬁrm non-allergy by OFC and this

would have contributed to an underestimation of

co-existent peanut/TN allergy.

Development of peanut/TN allergy

The age of participants may also play a role in

the rate of co-existent peanut/TN allergy. Indeed,

although most TN allergies become apparent

when a patient is young, many studies have shown

that the rate of co-existent allergy between peanut

and TN increases with age. The HealthNuts study

showed that children who had peanut allergy at 1

year old had a 27% chance of having an OFC-

conﬁrmed TN allergy at 6 years of age.

Brough

et al in a retrospective study reported similar

results.

This increase can be explained

particularly by the fact that nuts are introduced

later than other foods. Indeed, Clark and Ewan

showed that the number of nut consumption

increased with age (23% eating more than one

nut at 2 years, versus 73% by 10 years); they

postulated that this could lead to higher rates of

multisensitization (19% at 2 years, 86% at 5–14

years) and multiallergy (2% at 2 years to 47% at

14 years).

Conversely, Elizur et al proposed the

opposite hypothesis, that elimination of TN in

multiple-food-allergic patients could promote the

development of sensitization and allergy to TN

years later.

Peanut/TN co-sensitizations are

Volume 14, No. 1, Month 2021 3

Component Protein Family Co Sensitization/Cross Reactivity

Tree nut

Hazelnut

18,36

Cor a 1 PR-10

Cor a 2 Proﬁlin

Cor a 8 LTP Ara h 9, Jug r 3

Cor a 9 legumin

Cor a 11 Vicilin

Cor a 12 Oleosin

Cor a 13 Oleosin

Cor a 14 2S albumin

Cashew

18,36

Ana o 1 Vicilin Pis v 5

Ana o 2 Legumin Pis v 2

Ana o 3 2S albumin Pis v 1

Pistachio

18,36,158

Pis v 1 2S albumin Ana o 3

Pis v 2 Legumin Ana o 2

Pis v 3 Vicilin

Pis v 4

Pis v 5 Legumin Ana o 1

Walnut

36,110

Jug r 1 2S albumin Car i 1

Jug r 2 Vicilin

Jug r 3 LTP Cor a 8, Arah 9

Jug r 4 Legumin Car i 4

Jug r 5 PR-10

Jug r 6 Vicilin

Jug r 7 Proﬁlin

Pecan

18,36

Car i 1 2S albumin Jug r 1

Car i 2 Vicilin

Car i 4 Legumin Jug r 4

Almond

125

Pru du 1 PR-10

Pru du 2 PR-5

Pru du 3 LTP

Pru du 4 Proﬁlin Ara h 9, Cor a 8, Jug r 3

Pru du 5

Pru du 6 Legumin

(continued)

4Midun et al. World Allergy Organization Journal (2021) 14:100491

http://doi.org/10.1016/j.waojou.2020.100491

Component Protein Family Co Sensitization/Cross Reactivity

Brazil nut

18,36

Ber e 1 2S albumin

Ber e 2 Legumin

Legumes

Peanut

40,159,160

Arah 1 Vicilin Gly m 5

Arah 2 2S albumin Gly m 8

Arah 3 Legumin Gly m 6

Arah 4 Legumin Gly m 6

Arah 5 Proﬁlin Gly m 3, lup a 5

Arah 6 2S albumin

Arah 7 2S albumin

Arah 8 PR-10 Gly m 4

Arah 9 LTP Glym 1, Cor a 8, Jug r 3

Arah 10 Oleosin

Arah 11 Oleosin

Arah 12 Defensin Gly m 2

Arah 13 Defensin Gly m 2

Arah 14 Oleosin

Arah 15 Oleosin

Arah 16 LTP

Arah 17 LTP

Gly m 1 LTP Ara h 9

Gly m 2 Defensin Arah 12, 13

Gly m 3 Proﬁlin Arah 5, Lup a 5

Gly m 4 PR-10 Arah 8

Gly m 5 Vicilin Ara h1

Gly m 6 Legumin A ra h 3-4

Gly m 7

Gly m 8 2S albumin Ara h 2

Lupin

40,159,160

Lup a 1 Vicilin

Lup a vicilin Vicilin

Lup a 5 Proﬁlin

Lup an 11S Vicilin

(continued)

Volume 14, No. 1, Month 2021 5

common and distinguishing asymptomatic sensi-

tization from clinical food allergy is currently based

on OFCs, whicht may lead to life-threatening re-

actions. The clinical relevance of serological cross-

reactivity between peanut/TN therefore needs to

be better deﬁned.

Peanut/TN allergy has 2 main dimensions. One

is the cross-reactivity for the components, and

another is severity. Recent advances in the ﬁeld of

component resolved diagnostics (CRD) provides

the clinician with more information as to whether

the patient has secondary nut allergy due to pollen

food syndrome (also known as oral allergy syn-

drome) or primary nut allergy, more likely to lead

to systemic symptoms.

Co-allergy and co-sensitization

Indeed, there are different sensitization proﬁles

in peanut/TN allergy. Patients can be, therefore,

sensitized to different families of proteins within

the nut. The physico-chemical properties of the

proteins to which peanut/TN allergic patients may

be sensitized are responsible for allergic reactions

of varying severity. The most well-known protein

family is the seed storage protein family (eg, Ara h

2, Cor a 9, Cor a 14) responsible for severe

anaphylactic reactions, explained in part by their

thermostability and digestive resistance. Other

families of proteins that are also responsible for

severe reactions are the oleosins, defensin and LTP

family.

Other sensitization patterns can lead to less se-

vere symptoms in the majority of cases, such as the

reprensented sensitization to PR-10 and proﬁlins

family. This is due to the fact that these protein

families are degraded by heat and digestion.

Components, protein families and cross-

reactivity between components are referenced in

Table 2.

Structural homology

Allergies to certain well-deﬁned combinations

of nuts may be due to the presence of similar or

closely related epitopes. Such closely related epi-

topes are more common in phylogenetically

closely related nuts such as cashew and pistachio,

walnut and pecan,

13,24,35,36

peanut and

soybean.

34,37–40

Thus, the Pronuts and NutCracker studies found

that 97%–100% of pistachio and pecan allergic

children were allergic to cashew nut and walnut,

respectively.

11,30

Moreover, 64.2%–83.3% of

patient allergic to cashew or walnut were

respectively co-allergic to pistachio and

pecan.

11,30

In a retrospective study, Andorf and al

reported similar results.

Pistachio and cashew

nuts belong to the same Anarcadiaceae family

(homology 79% between rPis v 3 and rAna o 1,

and homology 66% between Pis v 1 and r Ana o

3).

13,41

High homology between pecan and

walnut protein sequences, which belong to the

same botanical family (the Juglandaceae family),

have also been described. Indeed, 2S albumin

allergens in walnut (Jug r 1) and pecan (Car i 1)

have 88% sequence identity and legumin

allergens in walnut (Jug r 4) and pecan (Car i 4)

have 95% sequence identity.

Component Protein Family Co Sensitization/Cross Reactivity

Seed

Sesame seed

161

Ses i 1 2 S albumin No available data

Ses i 2 2 S albumin No available data

Ses i 3 Vicilin No available data

Ses i 4 Oleosin No available data

Ses i 5 Oleosin No available data

Ses i 6 Legumin No available data

Ses i 7 Legumin No available data

Table 2. (Continued) PR-10: pathogenesis related protein type 10, LTP: lipid transfer protein.

6Midun et al. World Allergy Organization Journal (2021) 14:100491

http://doi.org/10.1016/j.waojou.2020.100491

Other studies have reported lower prevalence

of co-allergy between cashew nut and pistachio.

Indeed, Van der Valk et al and the HealthNut

studies found that only 31%–36% of the cashew-

allergic patients reacted to pistachio.

15,42

There

is an uni-directionality of the co-existent allergies,

as a lower proportion of patients allergic to walnut

and cashew are allergic to pecan and pistachio,

respectively. This suggests that some allergenic

proteins are shared while others are unique to

cashew and walnut and therefore result in mono-

allergy.

For peanut and soybean, studies have demon-

strated similarities between both legumes aller-

gens, such as Ara h 1, Ara h 3, and Ara h 8 with Gly

m 5, Gly m 6, and Gly m 4, respectively, between

38,4%–70%

34,37–40

(Table 2).Despite this

homology, studies show a low rate of cross

sensitization and cross reaction. Indeed, in a

study from several years ago, 31% of peanut-

allergic children had cosensitization with soy, and

only 3% had clinical reactivity to soy.

In other

studies, the cross-reactivity rate has been esti-

mated to be between 6.5% and 15%.

44,45

Another

study by Savage et al reported that 98% of patients

with a soy allergy also had a peanut allergy.

with nut allergies, these data suggest that some

proteins are common to peanut and soybean

and some are speciﬁc to soybean and peanut.

Protein families

Different families of proteins such as the seed

storage protein families (vicillins, 2 S albumins and

legumes), the family of lipid transfer proteins (LTP)

family, and pathogenesis-related protein type 10

(PR-10) family also help explain the cross-reactivity

among peanuts and other legumes (eg, peanut-

lupine). In addition, they also help explain, in

part, why unrelated nuts such as TN and peanuts

may exhibit serological and clinical cross-

reactivity.

3,26,27

Seed storage protein family

Peanut and lupine have a high degree of cross-

reactivity; therefore, risk associated with cross re-

action is also high as compared to other legumes.

Studies show that 14.5%–89% of peanut allergic

patients were sensitized to lupine however this

cross sensitivity is clinically signiﬁcant in only 4%–

35% of cases.

50–55

(Table 2). Cross-reactivity has

been reported to be mediated by Lup a 1 (vicilin-

like protein)

40,51

(Table 2). In 2017, the lupine

proﬁlin Lup a 5 was registered, which is highly

cross-reactive to other proﬁlins (eg, Ara h 5) and

which is recognized by the sera of both lupine and

peanut-allergic patients (www.allergome.org).

Lipid Transfer Protein family

Due to structural homology, lipd transfer pro-

teings (LTPs) from different allergen sources are

generally IgE cross-reactive; however, sensitization

proﬁles are extremely heterogeneous, and indi-

vidual cross-reactivity patterns may range from a

single LTP to many different LTPs (from food or

pollens).

56,57

Some studies report a signiﬁcant number of

peanut/TN allergies associated with LTP sensitiza-

tion, which may be responsible for severe systemic

reaction.

58,59

The peach LTP Pru p 3 has been

shown to be the primary sensitizing allergen for

cross-reactivity with other LTP, including peanut

(Ara h 9), hazelnut (Cor a 8), walnut (Jug r 3), and

almond (Pru du 3)

(Table 2). It has been shown

that sensitization to LTP leads to a large variety of

clinical manifestations; although oral allergy

syndrome (OAS) is probably the most frequent

clinical expression, LTPs can be also responsible

for severe systemic reactions.

57,58

Thus, it is the

most frequent cause of primary food allergy in

the Mediterranean area.

61,62

LTP sensitization can occur via the gastrointes-

tinal tract, but the predominant presence of the

LTP syndrome only in the Mediterranean region

suggests that environmental factors play a major

role. Indeed, Vereda et al showed that in peanut

allergic patients, LTP sensitization rate varied by

country: in Spain, 60% of patients are sensitized to

peanut LTP (Ara h 9) while these proportions were

7.7% and 14.3% in the United States and in Swe-

den, respectively.

The reasons for these

geographical distributions are still poorly

deﬁned. Studies hypothesize that these

distributions are in part due to variations in

environmental homologous pollen allergens

exposures in LTP-endemic areas such as Art v 3

from mugwort, or Pla a 3 from plane tree.

56,58

agreement with Pastorello,

Scala et al reported

that, in LTP allergic patients, co-sensitization with

PR-10 proteins, is associated with milder

symptoms.. In addition, the higher the levels of

Volume 14, No. 1, Month 2021 7

birch pollen in a certain area, the lower the

prevalence of LTP hypersensitivity.

PR-10 family

TN and peanut allergy may display serological

as well as clinical cross-reactivity with pollens.

The majority of these patients suffer from OAS.

Patients initially allergic to birch pollens through

sensitization to a PR-10 protein, may develop a

secondary allergy (pollen-food syndrome) to pea-

nuts or TN (OAS);

65,66

they develop mainly mild

symptoms limited to the oropharynx, with

pruritus, tingling, erythema, and mild edema of

the mouth upon ingestion of peanut or TNs(67).

Pollen food syndrome (PFS) is triggered by a

cross-reaction between allergens in pollen and

allergens in peanuts/TN.

65,66

Homologous

proteins have been identiﬁed between hazelnut,

walnut, peanut, and soybean and have been

shown to cross-react with Bet v 1.

68–70

The prevalence of PFS ranges from 4.7% to

greater than 20% in children sensitized to pol-

lens.

66,67

The PR-10 family also plays a signiﬁcant

role in PFS. Bet v 1 from birch pollen is well known

of these proteins

and is one of the major pan-

allergens in PFS.

Uotila et al in a retrospective

study found that among subjects with birch

sensitization, 84% were cosensitized to hazelnut,

71% to almond, and 60% to peanut; amongst

these nut-sensitized patients, 40% of patients

sensitized to hazelnut, 34% of those sensitized to

almond, and 36% of those sensitized to peanut

reported typical symptoms of PFS.

retrospective review from Northern France, where

there is a high level of birch pollen exposure,

reported a 43.2% co-existent TN allergy rate

amongst patients with peanut allergy (43,2%), with

hazelnut being the most common TN allergy

observed.

Symptoms associated with PR-10 sensitivity are

mainly mild.

69,71–73

However, the thermostability

of the proteins in this family are variable. Heat

processing such as roasting signiﬁcantly reduces

the rosacea fruit protein allergenicity in patients

with birch-pollen allergy, but some sensitized in-

dividuals can still experience positive reactivity

toward roasted peanut, soy, and TNs.

Diagnostics for peanut and tree nut allergy

Peanut and TN allergy is typically diagnosed

based on a combination of a convincing history of

a IgE mediated allergic reaction, SPT, serum-

speciﬁc IgE and, if necessary, an OFC.

74–77

For

example, peanut allergy is diagnosed based on

the clinical history of reaction, the presence of

risk factors (severe atopic dermatitis) and if

needed additional tests such as SPT, sIgE, and

component resolved diagnosis (CRD). Although

the cut-off points for determining allergy vary in

different regions/clinical settings, these tests have

led to a major improvement of the diagnosis of

peanut allergy. If history and allergy tests are

discordant, the gold standard for diagnosis of

food allergies is the double-blind, placebo-

controlled, food challenge (DBPCFC).

One of the major issues in clinical practice is the

difﬁculty in distinguishing asymptomatic sensitiza-

tion (false positives) from primary allergy and from

secondary allergy (PFS); this is particularly complex

for nut allergies due to the high prevalence of

pollen co-sensitization.

Double-blind, placebo-controlled, food challenge

Although the DBPCFC is the gold standard for

diagnosis of food allergies, this is costly, resource

and time-consuming, and carries the risk of

potentially life-threatening reactions. Some pa-

tients or their parents refuse to perform an OFC

due to the fear of triggering a severe reaction. In

the Pronuts study, Brough et al reported that 8.2%

of children did not perform an OFC due to fear of

reaction or history of previous severe reaction on

exposure to the incriminated nut.

In this clinical

setting, not performing an OFC can potentially

lead to unnecessary and prolonged peanut/TN

avoidance, which may have the unintended risk

of increasing peanut/TN allergy risk.

However,

it is necessary to ﬁnd new, less invasive

diagnostic tools for the diagnosis of peanuts/TN

allergies. Studies have shown that combination of

SPT, sIgE, and basophil activation test (BAT)

improved the ability to identify allergic and

tolerant patients. In the case of peanut allergic

patients, this approach could potentially lead to a

reduction of OFC of 76.6%–97%.

30,79

8Midun et al. World Allergy Organization Journal (2021) 14:100491

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SPT and speciﬁc IgE to whole extract allergen

As for other allergies, it is of major importance

to interpret peanut/TN SPT and sIgE in the context

of the clinical history. The diagnostic value of SPT

and speciﬁc IgE to whole allergen extracts has

been found to vary signiﬁcantly among studies.

Indeed, those different results might be explained

by differences in the population studied, preva-

lence of pollen allergy, and the methodology used

in the study.

30,65,80,81

These data have been

summarized in Table 3. As an example, while a

SPT <3 mm has a good negative predictive

value;

82–85

SPT<3 mm still requires further

investigations in the context of a convincing

clinical history of nut allergy. In contrast, a SPT

3 mm to a speciﬁc nut, without an appropriate

clinical context has a poor predictive value and is

associated with high rate of false

positives.

83,86,87

Clark et al showed that amongst

patients with a history of reaction to peanut or

TN, a SPT 8 mm had a predicted clinical

reactivity greater than 95% accuracy.

Ho et al

conﬁrmed this threshold value for cashew,

hazelnut, and walnut.

Speciﬁc IgE to whole allergen extracts of pea-

nut/TN are more widely available than SPTs and

improve the management of patients with a sus-

picion of nut allergy. However, similarly to SPT,

there is a large variation regarding the reported

diagnostic values of sIgE.

24,30,90–92

Data are

summarized in Table 3. As an example, Sampson

et al showed in the 1990s that a peanut sIgE

15kU/L could predict clinical reactivity with

greater than 95% certainty.

Clark et al

conﬁrmed and extended this result to TN

allergy.

88,94

Fleisher et al reported that only 63%

of patients with a history of clinical TN allergy

and TN sIgE levels <2 kU/L passed their OFC.

a retrospective study, Couch et al reported a

higher proportion of patients with a negative

OFC (89%) with similar levels of sIgE (<2kU/L).

Speciﬁc IgE and SPT are routinely performed as

aﬁrst-line procedure to support the diagnosis of

allergy; however, false negatives can occur. These

false negatives can be explained in part by the fact

that commercial extracts (SPT and sIgE) do not

contain extracts of oleosins (lipid-bound allergens)

that are responsible for some allergic reactions.

Modiﬁed skin prick testing (using the actual nut or

nut butter), or the use of CRD to measure oleosins

(e.g Ara h 10 and 11 for peanut) or in the baso-

philic activation test would therefore be valuable

diagnostic tools, but these data need to be

conﬁrmed by further studies.

Component resolved diagnosis

During the last decade, the introduction of CRD

has led to a major improvement in the diagnosis of

nut allergies.

18,78,96

It is now possible to identify patients who have

developed sIgE against seed storage proteins that

are associated with a high risk of systemic re-

actions. The most well-known example is sIgE to

Ara h 2, which is a peanut seed storage protein. It

has been shown that 80%–100% of patients with

primary peanut allergy are sensitized to Ara h

62,97–100

Cut-off decision points for Ara h 2 sIgE

have been determined in multiple studies, but

there is a large variation of the reported values

(Table 3). Hazelnut also contains seed storage

proteins, ie, Cor a 9 and Cor a 14, and sIgE to

these proteins have also been associated with

systemic reactions.

101,102

These tests have been

found to be highly speciﬁc and more sensitive

than sIgE and SPT to whole allergen extract to

diagnose a primary hazelnut allergy.

101

However,

there is again a large variation of reported

diagnostic values, particularly for sIgE to Cor a

14.

98,101–106

In addition, some studies have

highlighted speciﬁc factors affecting the variation

of the diagnostic values of sIgE to Cor a 9 and

Cor a 14. Particularly, the age of the child may

affect the diagnostic value of these tests. Thus, it

has been found that Cor a 9-sIgE speciﬁcity de-

creases with age, while Cor a 14-sIgE speciﬁcity

increases with age.

102,107,108

Speciﬁc IgE to seed

storage proteins found in other TNs (ie, Jug r 1,

Jug r 4 in walnut or Ana o 3 in cashew nut) have

also been found to improve diagnostic accuracy

of allergy to these nuts.

109–112

Regarding walnut,

sIgE to Jug r 1 and Jug r 4, were reported to

provide the best distinction between walnut

allergy and sensitization.

113,114

Indeed, sIgE to

Jug r 1 and Jug r 4 have been found to be

positive in 75% and in 56.7–66% of walnut

allergic patients, respectively.

115,116

The

NutCracker study found that IgE levels 0.35kU/L

to Jug r 1 and Jug r 4 provided the best

diagnosis method for identifying walnut allergic

Volume 14, No. 1, Month 2021 9

Food Cutoffs for sIgE to extract

allergen

Cutoffs for speciﬁc IgE to

main components

Cutoffs for speciﬁc skin

prick test

Peanut 15 kU/L, 95% PPV

162–164

4mm–15mm, 95%–

100% PPV

Ara h 2 sIgE: 0.35–42.2 kU/L had 90%–95%

PPV

79,98,99,165–168

Arah 8 : 0.6 kU/L to

100 kU/L

Arah 9: no available values

Hazelnut 0,7kU/L- 15 kU/L or greater

57%-92%PPV

92,102

8mm–17mm or

greater, 74%-100%

PPV

89,169

0,35kU/l, 95%NVP

102

Cor a 9 sIgE: 1 kU/L had 83%

accuracy

102

Cor a 14 sIgE: 0.72–47.8 kU/L

had 87%–90% accuracy

98,103

Cor a 1: no available values

Cor a 8: no available values

Walnut 5.07 kU/L 18,5kU/L or

greater, 95%–99% PPV

24,81

8 mm, 95%PPV

30,89

Jug r 1 sIgE: 0.1 kU/L had

91% PPV(113), 0,35kU/l,

accuracy 0,93(81)

Jugr 4 0,35kU/L, accuracy

0,93(81)

Jug r 3: no available values

Pecan 7 mm, 75% PPV

Cashew 8 kU/l –149.5kU/L or

greater: 95%PPV

89,170

8 mm, 95%PPV

10–12 mm, 95%

PPV

30,171

Ana o 3 sIgE: 0.16 kU/L had

97.1% accuracy for cashew

and/or pistachio nut

allergy

109

Pistachio 88 kU/l, 90% accuracy

Almond

Pru du 1 (PR-10)

Brazil nut 3,5kU/l 100% PPV

6 mm, PPV 100%

9 mm, accuracy

95%

Ber e 1 sIgE: 0.25 kU/L had

94% PPV

172

Table 3. PPV: positive predictive value, NPV: negative predictive value, PR-10: Pathogenesis related protein type 10.

10 Midun et al. World Allergy Organization Journal (2021) 14:100491

http://doi.org/10.1016/j.waojou.2020.100491

patients (accuracy 0,93) (Table 3). In addition, the

NutCracker study reported that patients with

walnut and pecan dual allergy were more

frequently sensitized to Jug r 4 compared to

patients with isolated walnut allergy.

Regarding

cashew nut, 2 European studies have shown that

up to 93% of children with cashew allergy are

sensitized to Ana o 3.

109,117

Ana o 3 sIgE level

0.16kU/L had 97.1% accuracy for cashew and/

or pistachio nut allergy.

109,117,118

(Table 3).

Speciﬁc IgE to Ana o 3 have been reported as a

highly accurate diagnosis marker also for

pistachio allergy.

36,109

Peanut/TN allergies may be the expression of a

sensitization to LTP family (eg, Arah 9, Cor a 8, Jug

r 3). Hazelnut has received the most extensive

evaluation. Studies reported that sensitization to a

hazelnut LTP (eg, Cor a 8) is a risk factor for

objective symptoms in children from a Mediterra-

nean region.

119–121

Hansen et al, in a multicenter

study performed in Switzerland, Spain, and

Denmark, reported that amongst patients with

hazelnut allergy, 28% had positive sIgE to rCor a

8. The highest rate of sensitization to the LTP rCor

a 8 was reported in Spain (71%), followed by

Switzerland (15%), then Denmark (5%). LTP

sensitization was present in 5 out of 7 patients

(71%) with severe symptoms to hazelnut and in

11 out of 52 patients (21%) with milder

reactions.

122

Diagnostic values of sIgE vary

signiﬁcantly between studies and cut-offs have

not been clearly established. There are many

confounding factors such as pollen inﬂuences,

patterns of sensitization (food or pollen) and

geographic distribution.

Distinction between primary and secondary al-

lergy is a challenge and use of CRD can help

differentiate phenotypes of peanut/TN allergy and

co-sensitization. Uotila et al found that in a birch

pollen endemic region, patients with peanut

sensitization without associated symptoms and

peanut allergic patients were equally sensitized to

PR-10 proteins (Bet v 1 90%). In this cohort, over

90% avoided TNs but only 6%–44% presented with

speciﬁc sensitizations to seed storage protein to

TNs.

123

Hence, an accurate diagnosis based on

CRD might have helped to decrease the rate of

unnecessary avoidance. Proteins of the PR-10

family have been identiﬁed for walnut (Jug r

5),

110

hazelnut (Cor a 1),

124

almond (Pru du 1),

125

and peanut (Ara h 8).

As with primary allergies,

the clinical expression of sensitization to PR-10

might be dependant on the speciﬁc IgE levels.

126

Basophil activation test

The BAT is another promising diagnostic tool for

nut allergy.

20,64

This test is not yet largely available

in the clinical setting, because it requires

appropriate equipment and trained personnel.

Thus, Santos et al proposed to restrict the use of

BAT to selected cases, for which the results of

routinely used tests do not allow a precise

diagnosis.

Several studies reported that in the

diagnosis of peanut/TN allergies, BAT had a

sensitivity ranging between 81.3% and 98%, and

a speciﬁcity ranging between 77 and

100%.

30,107,127

However, cut-offs determined for

the BAT can vary according to the population

studied, the design of the study, and the meth-

odology adopted for the BAT procedure and data

analyses.

Regarding peanut allergy, Santos et al and

Ocmant et al determined optimal cut-off points for

CD63 at 4.78% and 9.1%, respectively.

79,128

Basophil reactivity in peanut-allergic subjects was

found to be associated with the severity of

allergic reaction, and it has also been shown that

BATs may be useful in monitoring patients

undergoing OIT.

128–130

However, studies are still

needed to conﬁrm these results.

Studies evaluating the diagnostic value of the

BAT for TN allergy are limited. Regarding hazelnut

allergy, it has been found that the BAT has a

sensitivity ranging between 85% and 100% and

speciﬁcity ranging between 80% and 97%.

127,131–

133

Recently, it was suggested that the use of the

BAT in combination with SPT was useful for the

diagnosis of TN allergies. Preliminary results

report that the combination of BAT with SPT and

clinical co-existent allergy knowledge enable the

differentiation of co-allergenicity patterns in pa-

tients sensitized to walnut, pecan, cashew and

pistachio.

However, these data should be

examined in a prospective study with a larger

patient population. In addition, BAT has been

also shown to be potentially useful in identifying

the culprit allergen in cases of PFS.

131,134–136

Volume 14, No. 1, Month 2021 11

MANAGEMENT

The basic approach to peanut/TN allergy man-

agement does not defer from current manage-

ment approaches to other food allergies. It

includes short-term, immediate treatment of

symptoms after the exposure and long-term stra-

tegies assuring strict avoidance of culprit nut and

minimising risk of any future reactions.

The management of mild reactions has been

based on the same therapies for many years,

namely non-sedating antihistamines.

137

Epinephrine is the cornerstone and ﬁrst-line treat-

ment for anaphylaxis.

138

Early recognition of signs

of anaphylaxis and prompt administration of

epinephrine are absolutely key, and patients with

potential anaphylaxis to peanut/TN should have

easy access to epinephrine autoinjectors in the

community.

Improved understanding of the pathophysio-

logical mechanisms involved in allergic reactions

may give rise to additional useful treatments.

Vadas et al reported on the role of PAF and the

activity of PAF acethylhydrolase in anaphylactic

reactions.

139

Arias et al, in an experimental study

in peanut-sensitized mice, reported that PAF an-

tagonists signiﬁcantly decrease the duration and

severity of the anaphylactic reaction compared to

other therapeutics (histamine receptor antagonist,

5 lipooxygenase inhibitor). Indeed 83% of PAF-

treated versus 43% of untreated mice reached re-

covery within 120 min after peanut challenge. In

addition, they also report that the combination of

PAF receptor antagonists and histamine receptor

antagonists allows for better management and an

even more signiﬁcant reduction in the severity and

duration of the reaction.

140

Long-term strategies assuring avoidance of in-

dex nut are quite complex and require a multi-

disciplinary approach, involving good education of

patients and their families. This education involves

teaching parents and their children to read food

labels and recognise their allergen appropriately.

Identifying and clearly listing the most common

food allergens has become a legal requirement in

many countries, but practices differ throughout the

world. Many food companies also choose to add

Precautionary Allergen Labels (PAL), such as “may

contain”, but it is not always clear what these labels

mean, and consumers often do not fully under-

stand this.

Historically, the main management approach to

nut allergy was strict, blanket avoidance of all nuts

in all peanut and TN allergic patients. Although

avoiding all nuts simpliﬁes the management and

may decrease the risk of reactions secondary to

cross-contact or misidentiﬁcation, it has many pit-

falls. As peanut/TN are long-term allergies, pa-

tients must avoid all nuts (ie,. peanuts and TN)

even if they might be clinically tolerant to selective

nuts, which puts an additional and unnecessary

restriction on patients’diet and social activities,

which in turn reduces quality of life

141

and

increases anxiety levels.

Strict avoidance of all

nuts may lead to development of new allergies,

as well as nutritional consequences, and

inﬂuence growth, particularly in children with

other food allergies.

33,142–144

On the other hand, introducing selective nuts in

the diet of patients allergic to some types of nuts

can be complicated, requires multiple in-

vestigations, and often multiple in-hospital OFCs,

which are limited not only by the available re-

sources and time, but also carry risk, as reactions

occurring during these OFCs can be severe.

Another important safety aspect of selective nut

consumption is patients' and their families’ability

to correctly recognise and distinguish the correct

nuts themselves. A study involving 1105

participants conducted by Hostetler et al

investigated the ability of children and adults to

appropriately identify peanut/TNs. Participants

were shown 19 different pictures of peanuts and

TNs, and the mean number of correct responses

was only 8.4. There was a signiﬁcant difference

between children and adults, but parents with

nut allergic children did not perform any better

than parents of children without a known nut

allergy.

145

Healthcare professionals' approach to the mat-

ter of nut avoidance in peanut/TN allergies man-

agement has changed; patient populations and

their preferences have also changed. Patients and

their families prefer having more freedom in

making choices and tend to get more involved in

their management decisions and wish dietary re-

striction to have less repercussions on their daily

life. Management of their peanut/TN allergies

12 Midun et al. World Allergy Organization Journal (2021) 14:100491

http://doi.org/10.1016/j.waojou.2020.100491

should be tailored to each patient, taking into

consideration many aspects in addition to test re-

sults, such as age, history of previous reactions,

concomitant conditions, patients' and families’

understanding of their allergies, tendency towards

risk taking, anxiety level, quality of life, and ulti-

mately, what our patients and their families want as

part of shared decision making.

146

Building up immune tolerance in mainly peanut

but also TN allergies has been a major focus of food

allergy research over the past decade. The number

of double-blind placebo controlled trials (with

several trials including large numbers of partici-

pants) investigating oral, sublingual, and epicuta-

neous routes have showed this treatment approach

to be efﬁcacious in desensitizing the individual

(increasing their threshold dose of reactivity), with

quite a good safety proﬁle.

147–149

However, the

question of safety of different routes of peanut/TN

immunotherapy and the beneﬁt/risk ratio of this

type of treatment remains a concern. A systematic

review and meta-analysis published by Chu. et al

showed that patients undergoing peanut oral

immunotherapy (OIT) had a signiﬁcant increase in

anaphylaxis risk and frequency.

150

Authors

concluded that peanut OIT achieved a modest

degree of desensitization but caused more

allergic and anaphylactic reactions in participants

receiving treatment with peanut (albeit mostly

during the updosing phase in hospital), when

compared with the placebo group. On the other

hand, as much as other routes such as

epicutaneous or sublingual might have a better

safety proﬁle, they might not be as effective as the

oral route.

151

This question will not be answered

accurately unless large double-blind multiple arm

studies comparing different routes of peanut/TN

immunotherapy are performed.

Another approach to TN OIT would be using nut

clusters such as cashew/pistachio,

11,19

walnut/

pecan,

11,19

and pecan/walnut/hazelnut/

macadamia nuts

as a treatment approach.

Indeed, Elizur et al showed in their open label

study investigating efﬁcacy of walnut oral

immunotherapy in 73 participants in which 55

participants received active treatment, all children

with co-existing pecan allergy were also desensi-

tised to pecan and 93% of children who were co-

allergic to hazelnut were desensitised after their

course of OIT with walnut.

Although these results

seem promising, there is a lack of substantial

evidence, and this might be quite an interesting

and large area for future research.

Lastly, the question of TN allergy prevention still

remains open. There is quite substantial evidence

for the early introduction of peanuts being pro-

tective against development of peanut allergy in

high risk infants. The LEAP (Learning Early About

Peanut Allergy)randomised controlled trial

showed a relative reduction in school-aged peanut

allergy prevalence of 86.1% in peanut skin prick

test negative and 70% in skin prick positive infants

who started eating peanuts by the age of 11

months, when compared with the group who

avoided peanut.

152

This ﬁnding was sequentially

supported by the results from the EAT (Enquiring

about tolerance) study in the per protocol group

and in children with positive sIgE >0.1kU/

153,154

In addition, as the follow up LEAP-On

Study showed, this protective effect remained

beyond time of intervention, and 1 year of peanut

avoidance was not associated with an increase in

peanut allergy.

155

It is not known whether a similar approach to

tree nut allergy prevention would be effective, but

previous data looking into development of sensi-

tization/allergies to TN suggested this is likely.

Unfortunately, as the LEAP study has shown, early

introduction of peanut seems to be allergen spe-

ciﬁc and early peanut introduction was not effec-

tive in prevention of TN allergies.

156

There might

be a practical limitation to this approach. As the

prevention strategy requires an early intervention,

families might ﬁnd it difﬁcult to introduce the

required amounts of multiple TNs into the child's

daily diet, which could greatly inﬂuence the

success of prevention strategy. Other areas

targeting the skin for the prevention of food

allergies may be an alternative approach.

157

This

is certainly a very interesting ﬁeld for future

research.

CONCLUSION

The speciﬁc difﬁculty with peanuts and TN al-

lergies is the presence of cross-reactivity between

them, and with pollens, making diagnostic and

therapeutic management complex. Many diag-

nostic tools such as SPT, sIgE, CRD, and BAT are

available to help make an accurate diagnosis, but

Volume 14, No. 1, Month 2021 13

the OFC remains at the present time the gold

standard despite the drawbacks that this entails.

Healthcare practitioners often propose the avoid-

ance of the index nut or of all nuts, as decided with

the parent and child where appropriate. Peanut

speciﬁc immunotherapy has shown beneﬁts for

desensitization but not tolerance induction once

the treatment is stopped;

126

however, it is not

widely available clinically. Recently, studies have

also shown a beneﬁt of immunotherapy with

hazelnuts.

127–129

Regarding the primary

prevention of TN allergy, data are missing;

however, given the clear evidence for prevention

for peanut allergy through early peanut

introduction, it seems legitimate to also research

this area. Targeted research is still required to

answer some controversies in peanut and TN

allergy treatment and prevention.

Abbreviations

Tree nut: TN; Oral allergy syndrome: OAS; Component-

resolved diagnostic: CRD; Skin prick test: SPT; Pathogen-

esis related protein type 10: PR-10; Lipid transfer protein:

LTP; Oral food challenge: OFC; Double-blind, placebo-

controlled, food challenge: DBPCFC; Oral induction toler-

ance: OIT; Platelet-activating factor: PAF; Pollen-food syn-

drome: PFS; Precautionary Allergen Labels: (PAL)

Author's contribution

Elise Midun wrote the chapters: introduction, Proportion of

patients reacting to multiple nuts, Co-allergy and co-

sensitization, Diagnostics for peanut and tree nut allergy,

and Conclusion, Suzana Radulovic wrote the chapter:

Management. Helen Brough read and corrected the re-

view, Jean-Christoph Caubet read and corrected the

review.

Consent for publication

The authors consent to the publication of this review.

Associated data

Data Availability Statement and Ethics approval.

Not applicable.

Funding

Not applicable.

Declaration of competing interest

The authors have not declared any conﬂicts of interest in

connection with this article. Authors have not received

funding for this article.

Acknowledgements

We would like to thank Helen Brough and Suzanna

Radulovic for participating in the writing of this review.

Author details

Pediatric Allergy Unit, University Hospitals of Geneva and

University of Geneva, Rue Willy Donzé 6, 1205 Geneva,

Switzerland, University Lyon 1 Claude Bernard, 43

Boulevard Du 11-Novembre-1918, 69100, Villeurbanne,

France.

Paediatric Allergy Group, Department of Women

and Children's Health, King's College London, London,

United Kingdom, Paediatric Allergy Group, Peter Gorer

Dept of Immunobiology, School of Immunology &

Microbial Sciences, King's College London, Guys' Hospital,

London, United Kingdom, Children's Allergy Service,

Evelina Children's Hospital, Guy's and St. Thomas' Hospital

NHS Foundation Trust, London, United Kingdom.

Pediatric Allergy Unit, University Hospitals of Geneva and

University of Geneva, Rue Willy Donzé 6, 1205, Geneva,

Switzerland.

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Volume 14, No. 1, Month 2021 19

Tree Nut Allergy in Children—What Do We Know? —A Review

Article

Full-text available

Nov 2024

Food allergy represents a significant public health concern, with its prevalence increasing in recent decades. Tree nuts are among major allergenic foods, and allergies to them are frequently linked to severe and potentially life-threatening reactions. Data on the prevalence and natural history of tree nut allergy are limited. Primary nut allergy typically presents with rapid-onset IgE-mediated symptoms. Diagnosis can be confirmed by demonstrating a positive skin prick test (SPT), specific IgE (sIgE), or through an oral food challenge. Component-resolved diagnostics (CRD) can identify those with a high risk of anaphylaxis. The main management strategy involves avoiding the culprit allergen and treating symptoms after accidental exposure. New therapeutic options, such as sublingual immunotherapy, oral food immunotherapy, with or without omalizumab, and other monoclonal antibodies, are being investigated to modify tree nut allergy. Tree nut allergy is a lifelong disease with a low likelihood of resolution. The aim of this paper is to present the current data on the prevalence, diagnosis, natural history, and management options for tree nut allergy.

Peanut Allergy Diagnosis: Current Practices, Emerging Technologies, and Future Directions

Article

Full-text available

Feb 2025

Peanut allergy presents a significant and growing public health concern, marked by its increasing prevalence and potential for severe allergic reactions. Traditional diagnostic methods, such as skin prick testing and serum IgE assays, serve as cornerstone approaches but often fall short in specificity, sensitivity, and risk stratification. This has driven the development of innovative diagnostic technologies, including component-resolved diagnostics, basophil activation tests, bead-based epitope assays, molecular diagnostics, and artificial intelligence applications. These advancements promise greater diagnostic precision, improved patient stratification, and tailored management strategies. However, challenges such as high costs, accessibility issues, and the need for standardized protocols hinder their widespread clinical adoption. This review explores the evolution of peanut allergy diagnostics, comparing traditional and emerging methodologies, and discusses their clinical implications, limitations, and future directions. The integration of advanced technologies with established approaches holds the potential to revolutionize peanut allergy diagnosis and management, ultimately enhancing patient care and outcomes.

Tolerance of peanuts and tree nuts in Spanish children with exclusive sensitization to lipid transfer proteins

Article

Full-text available

Jul 2024
PEDIATR ALLERGY IMMU

Background Allergy to peanuts and tree nuts is a common cause of food allergy in Spain, with lipid transfer proteins (LTP) being the most frequently recognized panallergen. LTP sensitization often leads to multiple food group sensitivities, resulting in overly restrictive diets that hinder patient's quality of life. This study aimed to assess the tolerance of peanuts and tree nuts (hazelnuts and walnuts) in children sensitized to LTP, potentially mitigating the need for such diets. Methods This prospective study enrolled individuals diagnosed with allergy to peanuts, hazelnuts, or walnuts. Data were collected from medical records, including demographics and clinical history. Allergological assessment comprised skin prick tests using commercial extracts and the nuts in question, alongside measurements of total and specific IgE to nuts and their primary molecular components. Participants showing positive LTP sensitization without sensitization to seed storage proteins underwent open oral nut challenges. Results A total of 75 individuals labeled as allergic to peanuts, 44 to hazelnuts, and 51 to walnuts were included. All of them underwent an open oral provocation test with the incriminated nut, showing a high tolerance rate. Peanut was tolerated by 98.6% of patients, 97.72% tolerated hazelnut, and 84.3% tolerated walnut. Conclusion The findings suggest that the majority of patients allergic to peanuts, hazelnuts, or walnuts, due to LTP sensitization and lacking IgE reactivity to seed storage proteins, can tolerate these nuts. This supports the need for personalized nut tolerance assessments to avoid unnecessary dietary restrictions.

Current options in the management of tree nut allergy: A systematic review and narrative synthesis

Article

Full-text available

May 2024
PEDIATR ALLERGY IMMU

Tree nut allergy is a lifelong and potentially life‐threatening condition. The standard of care is strictly avoiding the culprit nut and treating accidental reactions symptomatically. To evaluate potential therapeutic options for desensitizing patients with IgE‐mediated tree nut allergy, we systematically searched three bibliographic databases for studies published until January 2024. We looked for active treatments of IgE‐mediated allergy to tree nuts (walnut, hazelnut, pistachio, cashew, almond, pecan, macadamia nut, and brazil nut). We focused on allergen‐specific immunotherapy (AIT) using oral (OIT), sublingual (SLIT), epicutaneous (EPIT), or subcutaneous (SCIT) delivery, or other disease‐modifying treatments. We found 19 studies that met our criteria: 3 studies investigated sublingual immunotherapy, 5 studied oral immunotherapy to a single tree nut, and 6 used multi‐food oral immunotherapy with or without omalizumab. The remaining studies investigated the effectiveness of monoclonal antibodies or IgE‐immunoadsorption in multi‐food allergic patients, including patients with tree nut allergy. The heterogeneity of the studies prevented pooling and meta‐analysis. Oral immunotherapy, single or multi‐nut, with or without omalizumab, was the most studied approach and appears effective in conferring protection from accidental exposures. Omalizumab monotherapy is the only approved alternative management for reducing allergic reactions that may occur with accidental exposure. image

Use of in vitro and in vivo tests in the diagnosis of food-induced anaphylaxis – a case study

Article

Dec 2023

Food allergy is a chronic disease that affects both children and adults. Systemic allergic reactions in children are most commonly caused by foods, especially nuts, milk, and eggs. A conventional diagnostic work-up for allergy typically pinpoints the allergen source, while component-resolved diagnostics is an approach that identifies the allergen molecules responsible for causing anaphylaxis. In some cases, determining the causative agent of anaphylaxis requires the use of various diagnostic tests. In the following paper, we want to highlight the importance of a critical approach to allergy tests results and caution in the diagnosis of idiopathic anaphylaxis. Based on a case report of food-induced anaphylaxis, we discuss the diagnostic methods that can be applied following a negative IgE test result for allergens obtained with a multiplex platform.

Allergie aux fruits à coque chez l’enfant : quelle prise en charge en pratique

Article

Jan 2025
REV FR ALLERGOL

Rapid Gluten Allergen Detection Using an Integrated Photoimaging Assay and Ionic Liquid Extraction Sensor

Article

Full-text available

Dec 2024

In recent years, food allergies and food sensitivities have remained critical public health problems that affect approximately 15% of the global population. Wheat is a major food source worldwide, but it is also a common food allergen. Celiac disease is chronic immune-mediated enteropathy triggered by exposure to dietary gluten in genetically predisposed individuals; it can be treated only through strict gluten avoidance. Therefore, rapid gluten detection is crucial for protecting the health of patients. Gluten contains two primary water-insoluble proteins: gliadin and glutenin. Gliadin is a key contributor to celiac disease and poses challenges for sample pretreatment owing to its insolubility, thereby reducing the accuracy and sensitivity of detection systems. Rapid sample processing is a critical problem in gliadin detection. In this report, we developed a gliadin sensor system called the integrated food allergy and microorganism sensor (iFAMs). The iFAMs comprises a gliadin lateral flow chip, a one-pot extraction solution, and an image assay app. The iFAMs enables gliadin extraction and detection in under 2 min with high sensitivity (0.04 mg/kg for gliadin, lower than the regulatory limit of 20 mg/kg). Users can easily measure gluten concentrations in samples and quantify gliadin levels using the smartphone-based image assay app. In samples collected from restaurants, the iFAMs successfully detected hidden gluten within “gluten-free” food items. The compact size and user-friendly design of the iFAMs render it suitable for not only consumers but also clinicians, food industries, and regulators to enhance food safety.

Development of Cashew and Pistachio Ladders through a Food-Processing Approach

Article

Full-text available

Oct 2024

Following successful oral immunotherapy (OIT) for peanut allergy using boiled peanuts (BOPI trial), this study investigated the potential of wet-thermal-processing-induced allergen modification, specifically soaking and boiling (1–4 h) to reduce the allergenicity of cashew and pistachio allergens. In addition, this study provides a foundation of understanding for developing safer forms of cashew/pistachio administration for application in OIT by gradual exposure to increasing doses of modified allergens with reduced potency as an “allergen ladder”. An SDS-PAGE analysis and an intrinsic-fluorescence spectroscopy revealed altered tertiary structures of the allergens, leading to their denaturation and even degradation. Notably, the reduction in both allergen-specific polyclonal IgG and human-specific IgE (sIgE) binding correlated with the treatment time, with the most significant decrease observed after 4 h of boiling. In contrast, shorter soaking treatments showed negligible effects on the IgE-binding capacity of these nuts, therefore indicating a further need for optimization. These findings indicate that extended boiling effectively reduced the amounts of the highly potent allergenic component Ana o 3 in cashew and Pis v 1 in pistachio, as confirmed by ELISA using polyclonal anti-Ana o 3 antibodies, and an immunoblot showed decreased IgE epitope binding in cashew and pistachio allergens, which further modified their allergenic profiles. This approach shows promise as a viable method for offering a safer therapeutic option for cashew/pistachio allergy.

Closed-tube saltatory rolling circle amplification assay for rapid and visual detection of allergenic cashew nut in foods

Article

Jul 2024
FOOD CONTROL

A comprehensive review on mango allergy: Clinical relevance, causative allergens, cross‐reactivity, influence of processing techniques, and management strategies

Article

Full-text available

Feb 2024
COMPR REV FOOD SCI F

Mangoes (Mangifera indica) are widely prized for their abundant nutritional content and variety of beneficial bioactive compounds and are popularly utilized in various foods, pharmaceuticals, and cosmetics industries. However, it is important to note that certain proteins present in mango can trigger various allergic reactions, ranging from mild oral allergy syndrome to severe life‐threatening anaphylaxis. The immunoglobulin E‐mediated hypersensitivity of mango is mainly associated with three major allergenic proteins: Man i 1 (class IV chitinase), Man i 2 (pathogenesis‐related‐10 protein; Bet v 1‐related protein), and Man i 4 (profilin). Food processing techniques can significantly affect the structure of mango allergens, reducing their potential to cause allergies. However, it is worth mentioning that complete elimination of mango allergen immunoreactivity has not been achieved. The protection of individuals sensitized to mango should be carefully managed through an avoidance diet, immediate medical care, and long‐term oral immunotherapy. This review covers various aspects related to mango allergy, including prevalence, pathogenesis, symptoms, and diagnosis. Furthermore, the characterization of mango allergens and their potential cross‐reactivity with other fruits, vegetables, plant pollen, and seeds were discussed. The review also highlights the effects of food processing on mango and emphasizes the available strategies for managing mango allergy.

A Retrospective Study of Peanut and Tree Nut Allergy: Sensitization and Correlations with Clinical Manifestations

Article

Full-text available

Jan 2015

Peanut (PN) and tree nut (TN) allergies are among the leading causes of fatal food-induced anaphylaxis and are increasing in prevalence, especially in children. Their cosensitization and concurrent clinical allergy have been understudied. This retrospective study investigated the correlation between PN and TN allergy, both in terms of in vitro sensitization (IVS) and clinical allergic manifestations. We conducted a retrospective medical record review at the Allergy Clinic at University Hospital of Brooklyn. Fourteen hundred six charts were reviewed, of which 76 (5.4%) had documented relevant clinical allergy: PN allergy but not TN allergy (n = 29) or TN allergy but not PN allergy (n = 11) or both (n = 30). Six patients with PN allergy but no TN exposure history were not included in the analysis. The majority of patients (67/76, 88.1%) had a concurrent history of asthma, rhinoconjunctivitis, or AD. Sensitivity of TN IVS predicting PN IVS was 38/39 (97%). Similarly, sensitivity of PN IVS predicting TN IVS was 38/42 (91%). Sensitivity of TN clinical allergy predicting PN allergy was 30/59 (51%). Sensitivity of PN clinical allergy predicting TN allergy was 30/41 (73%). The total number of organ systems involved in reported clinical reactions correlated with IVS to TN (p = 0.004) but not IVS to PN (p = 0.983). In summary, we found PN sensitization predicts TN sensitization in vitro, with lower predictability for clinical reactions.

Epicutaneous sensitization in the development of food allergy: What is the evidence and how can this be prevented?

Article

Full-text available

May 2020
ALLERGY

There is increasing evidence regarding the importance of allergic sensitization through the skin. In this review, we provide an overview of the atopic march and immune mechanism underlying the sensitization and effector phase of food allergy. We present experimental models and human data that support the concept of epicutaneous sensitization and how this forms one half of the dual‐allergen exposure hypothesis. We discuss specific important elements in the skin (FLG and other skin barrier gene mutations, Langerhans cells, type 2 innate lymphoid cells, IL‐33, TSLP) that have important roles in the development of allergic responses as well as the body of evidence on environmental allergen exposure and how this can sensitize an individual. Given the link between skin barrier impairment, atopic dermatitis, food allergy, allergic asthma, and allergic rhinitis, it is logical that restoring the skin barrier and prevention or treating atopic dermatitis would have beneficial effects on prevention of related allergic diseases, particularly food allergy. We present the experimental and human studies that have evaluated this approach and discuss various factors which may influence the success of these approaches, such as the type of emollient chosen for the intervention, the role of managing skin inflammation, and differences between primary and secondary prevention of atopic dermatitis to achieve the desired outcome.

Efficacy of the Enquiring About Tolerance (EAT) study among infants at high risk of developing food allergy

Article

Full-text available

Dec 2019
J ALLERGY CLIN IMMUN

Background: The Enquiring About Tolerance (EAT) study was a randomized trial of the early introduction of allergenic solids into the infant diet from 3 months of age. The intervention effect did not reach statistical significance in the intention-to-treat analysis of the primary outcome. Objective: We sought to determine whether infants at high risk of developing a food allergy benefited from early introduction. Methods: A secondary intention-to-treat analysis was performed of 3 groups: nonwhite infants; infants with visible eczema at enrollment, with severity determined by SCORAD; and infants with enrollment food sensitization (specific IgE ≥0.1 kU/L). Results: Among infants with sensitization to 1 or more foods at enrollment (≥0.1 kU/L), early introduction group (EIG) infants developed significantly less food allergy to 1 or more foods than standard introduction group (SIG) infants (SIG, 34.2%; EIG, 19.2%; P = .03), and among infants with sensitization to egg at enrollment, EIG infants developed less egg allergy (SIG, 48.6%; EIG, 20.0%; P = .01). Similarly, among infants with moderate SCORAD (15-<40) at enrollment, EIG infants developed significantly less food allergy to 1 or more foods (SIG, 46.7%; EIG, 22.6%; P = .048) and less egg allergy (SIG, 43.3%; EIG, 16.1%; P = .02). Conclusion: Early introduction was effective in preventing the development of food allergy in specific groups of infants at high risk of developing food allergy: those sensitized to egg or to any food at enrollment and those with eczema of increasing severity at enrollment. This efficacy occurred despite low adherence to the early introduction regimen. This has significant implications for the new national infant feeding recommendations that are emerging around the world.

Correlation of negative skin-prick test results for tree nuts and successful tree nut challenges among children with peanut allergy

Article

Dec 2018

Background: Children with peanut allergy are regularly instructed to avoid all tree nuts. However, children with peanut allergy are likely not allergic to all tree nuts. Objective: In our cohort of patients with peanut anaphylaxis and who underwent oral immunotherapy, we sought to determine the correlation of skin-prick testing (SPT) results for tree nuts and the likelihood of successfully passing a tree nut challenge. Methods: SPT was performed for peanut and tree nuts (macadamia, pine nut, coconut, hazelnut, brazil nut, cashew, pecan, walnut, pistachio, almond) in 27 patients with known peanut allergy. The probability of a negative SPT result (wheal 3 mm) for each nut was determined. Results: All the patients demonstrated positive results in peanut allergy diagnostics in SPT, component testing, or food challenge. Only 15.4% of the patients had a positive SPT result to peanut alone. Macadamia, pine nut, and coconut SPT had a probability of negative SPT results of 0.97, 0.97, and 0.91, respectively. The odds ratio for this group having a negative SPT was 46.22. For hazelnut, brazil nut, and cashew, the probability of a negative SPT result was 0.81, 0.77, and 0.73, respectively. Pecan, walnut, and pistachio had odds ratios of 0.68, 0.68, and 0.64, respectively. All the patients with macadamia, pine nut, and coconut negative SPT results subsequently passed 9-g food challenges without oral immunotherapy. Conclusion: Despite current recommendations to avoid all tree nuts for patients with peanut allergy, the majority of patients with peanut allergy had negative SPTs and food challenges to certain tree nuts, especially macadamia, pine nut, and coconut. This pattern was seen despite most patients having multiple nut sensitizations.

Skin Prick Test Predictive Values for the Outcome of Cashew Challenges in Children

Article

Jan 2020

Prevalence and natural history of tree nut allergy

Article

Feb 2020

Objective: Tree nuts are common causes of food related allergic reactions and anaphylaxis. Resolution of tree nut allergy is thought to be low yet studies of the natural history of tree nut allergy are limited. This review summarizes the available literature regarding tree nut allergy prevalence and natural history, and discusses emerging diagnostic and prognostic developments that will inform clinical management of tree nut allergy. Data sources: A comprehensive literature search using PubMed was performed. Study selections: Peer-reviewed publications relating to tree nut allergy prevalence, resolution and diagnosis were selected, and findings summarised using a narrative approach. Results: Tree nut allergy prevalence varies by age, region and food allergy definition, and ranges from less than 1% to around 3% worldwide. Reports on the natural history of tree nut allergy data are limited to retrospective clinical data or cross-sectional survey data of self-reported food allergy with reported resolution ranging from 9-14%. Component resolved diagnostics and basophil activation testing offer the potential to improve the diagnostic accuracy and predicted prognosis of specific tree nut allergy but studies are limited to date. Conclusion: Tree nut allergy remains an understudied area of food allergy research with limited region specific studies based on robust food allergy measures in population cohorts with longitudinal follow up. This currently limits our understanding of tree nut allergy prognosis.

Significantly Increased Threshold Dose After Long-Term Peanut Epicutaneous Immunotherapy and Daily Oral Peanut Intake

Article

Jan 2020

Anaphylaxis – a 2020 Practice Parameter Update, Systematic Review and GRADE Analysis

Article

Jan 2020
J ALLERGY CLIN IMMUN

Anaphylaxis is an acute, potential life-threatening systemic allergic reaction that may have a wide range of clinical manifestations. Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis. Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis, although evidence supports a role for antihistamine and/or glucocorticoid premedication in specific chemotherapy protocols and rush aeroallergen immunotherapy. Evidence is lacking to support the role of antihistamines and/or glucocorticoid routine premedication in patients receiving low- or iso-osmolar contrast material to prevent recurrent radiocontrast media anaphylaxis. Epinephrine is the first-line pharmacotherapy for uniphasic and/or biphasic anaphylaxis. After diagnosis and treatment of anaphylaxis, all patients should be kept under observation until symptoms have fully resolved. All patients with anaphylaxis should receive education on anaphylaxis and risk of recurrence, trigger avoidance, self-injectable epinephrine education, referral to an allergist, and be educated about thresholds for further care.

Defining challenge-proven coexistent nut and sesame seed allergy: A prospective multicenter European study

Article

Dec 2019
J ALLERGY CLIN IMMUN

Background: Peanut, tree nut, and sesame allergies are responsible for most life-threatening food-induced allergic reactions. Rates of coexistent allergy between these foods have been from mostly retrospective studies that include only a limited number of tree nuts or were not based on oral food challenges. Objective: The Pronuts study is a multicenter European study (London, Geneva, and Valencia) assessing the challenge-proven rate of coexistent peanut, tree nut, and/or sesame seed allergy. Methods: Children aged 0 to 16 years with at least 1 confirmed nut or sesame seed allergy underwent sequential diagnostic food challenges to all other nuts and sesame seed. Results: Overall, the rate of coexistent peanut, tree nut, and sesame seed allergy was 60.7% (n = 74/122; 95% CI, 51.4% to 69.4%). Peanut allergy was more common in London, cashew and pistachio nut allergies were more common in Geneva, and walnut and pecan allergies were more common in Valencia. Strong correlations were found between cashew-pistachio, walnut-pecan, and walnut-pecan-hazelnut-macadamia clusters. Age (>36 months) and center (Valencia > Geneva > London) were associated with an increased odds of multiple nut allergies. By pursuing the diagnostic protocol to demonstrate tolerance to other nuts, participants were able to introduce a median of 9 nuts. Conclusion: We found a higher rate of coexistent nut and sesame seed allergies than previously reported. Performing sequential food challenges was labor intensive and could result in severe allergic reactions; however, it reduced dietary restrictions. Age was a significant predictor of multiple nut allergies, and thus the secondary spread of nut allergies occurred in older children.

The Role of Shared Decision Making in Pediatric Food Allergy Management

Article

Sep 2019

Shared decision-making was first highlighted in a report by the Institute of Medicine in 2001. The primary aim of this initiative was to improve the quality of care provided to patients in the United States by creating a health care system that is safe, effective, efficient and equitable. Currently, medical decision making is based on a patient-centered approach with the individuals' preferences, needs and values guiding optimal care. Patients are frequently faced with a variety of treatment choices with no absolute guarantee of any desired outcome and no clear indication of the 'best or least worse" option. In fact, in healthcare, each of these options, usually have potential trade-offs and outcomes. The process of how to choose a particular option becomes a discussion where the clinician and the patient have to jointly review the medical evidence, but also the patient's openness and preference for balancing particular attributes of the treatment (both positive and negative). Shared decision-making is important for chronic diseases that require long-term management, such as most allergic conditions, including food allergies. The landscape of food allergies has changed considerably in recent years with multiple and significant scientific advances in both diagnostics and treatment, providing an ideal field for the use of shared decision-making. For the purposes of this review, we will discuss different areas of food allergy management within a single complex case, focusing on the role of shared decision-making.