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open access to scientific and medical research

Open Access Full Text Article

http://dx.doi.org/10.2147/JAA.S49277

Diagnosis and management of food allergies: new and emerging options: a systematic review

Andrew w O’Keefe1,2

Sarah De Schryver1

Jennifer Mill3

Christopher Mill3

Alizee Dery1

Moshe Ben-Shoshan1

1Division of Pediatric Allergy and Clinical immunology, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada; 2Department of Pediatrics, Faculty of Medicine, Memorial University of Newfoundland, St John’s, NL, Canada; 3Division of Clinical epidemiology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada

Correspondence: Andrew w O’Keefe Janeway Children’s Hospital, Department of Pediatrics, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St John’s, NL A1B 3v6, Canada Tel +1 709 777 4302 Fax +1 709 777 4736 email okeefe.andy@gmail.com

Abstract: It is reported that 6% of children and 3% of adults have food allergies, with studies

suggesting increased prevalence worldwide over the last few decades. Despite this, our diag-

nostic capabilities and techniques for managing patients with food allergies remain limited.

We have conducted a systematic review of literature published within the last 5 years on the

diagnosis and management of food allergies. While the gold standard for diagnosis remains

the double-blind, placebo-controlled food challenge, this assessment is resource intensive and

impractical in most clinical situations. In an effort to reduce the need for the double-blind,

placebo-controlled food challenge, several risk-stratifying tests are employed, namely skin

prick testing, measurement of serum-specific immunoglobulin E levels, component testing, and

open food challenges. Management of food allergies typically involves allergen avoidance and

carrying an epinephrine autoinjector. Clinical research trials of oral immunotherapy for some

foods, including peanut, milk, egg, and peach, are under way. While oral immunotherapy is

promising, its readiness for clinical application is controversial. In this review, we assess the

latest studies published on the above diagnostic and management modalities, as well as novel

strategies in the diagnosis and management of food allergy.

Keywords: skin prick testing, oral challenge, specific IgE, component testing, oral immuno-

therapy, epinephrine autoinjector

IntroductionEuropean studies estimate the lifetime prevalence of food allergy is 17.3% and the

point prevalence 6%.1 Recent studies suggest an increased prevalence worldwide

over the last few decades of food allergy and food-induced anaphylaxis.2,3 Despite the

increasing prevalence of food allergy, our diagnostic and management strategies have

remained relatively unchanged over time. The double-blind, placebo-controlled food

challenge (DBPCFC) is considered the gold standard for diagnosis of food allergies,

but is rarely employed by physicians outside of an academic context. It is estimated

that DBPCFCs have a false negative rate ranging from 2%–5% and a false positive

rate near 5.4%–12.9%.4 The open food challenge (OFC) is a more viable option for

most clinicians, though it is not without its own pitfalls.

Most clinicians rely on skin prick testing (SPT) and serum-specific immunoglobulin E

(sIgE) testing to establish the diagnosis of food allergy. SPT is readily performed in

the clinical setting, and a near infinite number of foods can be evaluated, although

extracts are not yet standardized. It is typically the first test used in the evaluation of

food allergy. Measurement of sIgE for a wide variety of foods is available in most

centers. These tests both evaluate the presence of IgE, which determines sensitization

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142

O’Keefe et al

but does not necessarily correlate with clinical reactivity.

In an effort to improve diagnostic accuracy, component

testing allows the allergist to examine IgE levels against a

particular protein of the culprit food. Examining sensitiza-

tion profiles to specific food allergen components aims to

distinguish between sensitized and truly reactive patients.5

Some proposed novel diagnostic tests are in development,

but are not yet ready for clinical application.

Management of food allergy relies primarily on aller-

gen avoidance, with prompt emergency care for accidental

exposure. Food allergen avoidance is not always effective,

as allergens such as milk and egg may be hidden in foods.

An estimated 10%–20% of individuals with a diagnosis of

anaphylaxis experience recurrent reactions.3,6,7 Despite clear

guidelines advising prompt use of an epinephrine autoin-

jector (EAI) in anaphylaxis, many patients and families do

not use an EAI, possibly due to inadequate knowledge and

anxiety.8,9 Moreover, the diagnosis of food allergy and the

need to carry an EAI are associated with negative effects

on quality of life for patients and families alike.10 A recent

review found that there were no robust studies examining

the effectiveness of injectable epinephrine, antihistamines,

systemic glucocorticosteroids, or methylxanthines in the

management of anaphylaxis.11 As prompt use of an EAI is the

most important step in the acute management of anaphylaxis,

we have focused on this treatment modality. Depending on

the allergen, many individuals will have lifelong food aller-

gies. Hence, it would be advantageous to have a treatment

strategy that allows for food reintroduction and obviates

the need to carry an EAI. As such, recent developments

in immunotherapy for foods are a very exciting prospect.

Incorporating baked milk and egg in the diet may be viewed

as a form of immunotherapy for these allergens, while there

are other protocols under investigation to desensitize and

potentially induce tolerance through gradual introduction

of the raw allergen. Other allergens under investigation as

candidates for immunotherapy include peanut and peach. In

this systematic review, we aim to assess existing and new

diagnostic modalities and management options for food

allergy. In particular, we will focus on literature published

in the last 5 years.

MethodsWe searched the PubMed database for scientific literature

published between January 13, 2009 and January 13, 2014

using the following search criteria: “food allergy” AND

“management” OR “diagnosis”. We used the following fil-

ters in our search: clinical trial, abstract available, and studies

done on humans in any language. Of the available articles,

we selected those that were relevant to this review based

on the abstract. A team of six readers then further reviewed

these articles. The articles have been summarized in regard

to food allergy diagnosis and management in Tables 1 and 2,

respectively. Upon initial search of PubMed using the above

terms, 12,139 titles appeared. After applying the filters as

described, 217 titles remained. Once abstracts had been

reviewed, 100 articles were warranted for inclusion in the

study (Figure 1).

DiagnosisSPTSPT is the primary diagnostic modality employed by most

allergists. It is relatively inexpensive, can be done in the

office, results are available immediately, and almost any

food can be tested in this manner. Typically, an extract or

fresh food is placed on the volar aspect of the forearm and

the skin is pricked with an instrument. Fresh food testing

can also be accomplished using the “prick-to-prick” method,

where the testing device first pricks the food to be tested and

is then used to prick the patient. A positive test will result

in wheal formation and erythema, indicating sensitization

to the allergen tested. Two studies have examined the use

of end-point prick testing, or using dilutions of extract or

fresh food in SPT, in predicting the outcome of the OFC. In

a cohort of patients known to be milk allergic, Bellini et al12

reported that SPT with a wheal diameter greater than 4.5

mm with a 1/10,000 dilution of fresh milk was the best test

for discriminating between milk-tolerant and milk-reactive

subjects. They proposed using diluted milk after SPT with

milk extract to help decide who should proceed to the OFC,

noting that those with a positive SPT to the 1/10,000 dilu-

tion should avoid the challenge. However, their results reveal

that 50% of children with a negative SPT response to diluted

milk will have a positive challenge. Tripodi et al13 conducted

a similar study using egg extract; however, their results may

not be reproducible as extracts were not standardized and

may have contained different levels of allergen. Johannsen

et al14 evaluated SPT and sIgE to peanut as predictors of OFC

outcomes in sensitized preschoolers, demonstrating that 50%

of sensitized children could safely ingest peanut. Further,

with a combined SPT wheal diameter of ,7 mm and sIgE

,2 kUA/L for peanut, there is a 5% chance they will react

to an OFC. It is reported that a SPT wheal diameter of 8 mm

as the threshold for sesame.15 Other researchers suggest a

SPT wheal diameters of 8 mm and 7 mm for milk and egg

thresholds, respectively.16

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143

Optimal diagnosis and management of food allergies

Tab

le 1

Dia

gnos

is o

f foo

d al

lerg

y

Mod

alit

yA

llerg

enT

ype

of

stud

yA

utho

rs,

publ

icat

ion

year

Ref

eren

ceFi

ndin

gsC

omm

ents

SPT

Milk

Ret

rosp

ectiv

e

coho

rtBe

llini

et

al, 2

011

12U

sed

end-

poin

t pr

ick

test

to

help

pre

dict

res

ults

of O

FC

in m

ilk-a

llerg

ic c

hild

ren.

whe

al d

iam

eter

.4.

5 m

m in

SPT

w

ith a

1/1

0,00

0 di

lutio

n of

fres

h m

ilk w

as b

est

able

to

di

scri

min

ate

milk

-alle

rgic

pat

ient

s fr

om t

oler

ant

ones

.

end-

poin

t tit

ratio

n is

an

acce

ssib

le a

nd s

afe

test

and

sh

ould

be

cons

ider

ed in

the

dia

gnos

is o

f milk

alle

rgy.

T

his

stud

y us

ed a

coh

ort

of p

atie

nts

with

kno

wn

milk

al

lerg

y, s

o re

sults

may

not

be

gene

raliz

able

.SP

T a

nd

spec

ific

IgE

Pean

utPr

ospe

ctiv

e

coho

rtJo

hann

sen

et a

l,

2011

14St

udy

of 4

9 pr

esch

oole

rs w

ith p

eanu

t se

nsiti

zatio

n bu

t

unkn

own

reac

tivity

. Hal

f of t

he c

hild

ren

reac

ted

to c

halle

nge.

SP

T w

heal

dia

met

er o

f .7

mm

pre

dict

ed p

ositi

ve c

halle

nge

w

ith 8

3% s

ensi

tivity

and

84%

NPV

. Spe

cific

IgE

.2

kUA

/L

show

ed s

ensi

tivity

of 7

9% a

nd 8

0% N

Pv. U

sing

a c

ombi

natio

n

of S

PT a

nd s

peci

fic Ig

E, r

esul

ts in

crea

sed

sens

itivi

ty t

o 96

%

and

NPv

to

95%

.

Hal

f of p

eanu

t-se

nsiti

zed

pres

choo

lers

will

pas

s O

FC.

if SP

T w

heal

dia

met

er is

,7

mm

and

spe

cific

IgE

,2

kUA

/L, t

here

is a

5%

cha

nce

of r

eact

ion

to t

he O

FC.

SPT

egg

Cro

ss-

sect

iona

lT

ripo

di e

t al

, 200

913

1:25

6 di

lutio

n of

egg

ext

ract

use

d fo

r SP

T w

ith w

heal

siz

e

.3

mm

was

95%

spe

cific

and

100

% s

ensi

tive

in

dist

ingu

ishi

ng a

pos

itive

from

a n

egat

ive

OFC

.

As

extr

acts

are

not

sta

ndar

dize

d, t

hese

stu

dy r

esul

ts

may

not

be

repr

oduc

ible

.

SPT

and

sp

ecifi

c Ig

EM

ilk a

nd

egg

Ret

rosp

ectiv

e

coho

rtM

ehl e

t al

, 201

217

23%

of c

hild

ren

with

milk

alle

rgy

had

disc

orda

nt S

PT a

nd

spec

ific

IgE

resu

lts, a

s di

d 10

% w

ith e

gg a

llerg

y. F

or m

ilk-

alle

rgic

chi

ldre

n w

ith a

pos

itive

OFC

, 84%

had

a p

ositi

ve

SPT

res

pons

e (w

heal

.3

mm

) an

d 87

% h

ad s

peci

fic Ig

E

.0.

35 k

UA

/L. F

or e

gg-a

llerg

ic c

hild

ren,

93%

with

a p

ositi

ve

SPT

res

pons

e ha

d a

posi

tive

OFC

, and

96%

with

pos

itive

ch

alle

nge

had

spec

ific

IgE

.0.

35 k

UA

/L.

SPT

and

spe

cific

IgE

shou

ld n

ot b

e us

ed

inte

rcha

ngea

bly.

Low

thr

esho

lds

wer

e us

ed t

o qu

alify

a

posi

tive

SPT

or

spec

ific

IgE

in t

his

stud

y.

Spec

ific

IgE,

co

mpo

nent

te

stin

g

Pean

utC

ross

- se

ctio

nal

Chi

ang

et a

l, 20

1022

89.5

% o

f Asi

an c

hild

ren

with

pea

nut

alle

rgy

had

dete

ctab

le

Ara

h 1

or

Ara

h 2

.M

ilk a

nd e

gg S

PT a

nd s

ige

leve

ls a

ssoc

iate

d w

ith a

po

sitiv

e O

FC w

ere

sim

ilar

in A

sian

chi

ldre

n w

ith

pean

ut a

llerg

y an

d w

este

rn c

ount

erpa

rts.

Thi

s st

udy

did

not

confi

rm p

eanu

t al

lerg

y w

ith o

ral c

halle

nge.

Spec

ific

IgE

Pean

utC

ross

- se

ctio

nal

van

Nie

uwaa

l et a

l,

2010

1890

% fa

iled

pean

ut c

halle

nge

at s

peci

fic Ig

E 24

.8 k

UA

/L, a

nd

95%

faile

d at

43.

8 kU

A/L

.Th

is st

udy

repo

rted

hig

her

spec

ific

IgE

cuto

ff le

vels

than

ot

hers

, per

haps

due

to e

xam

inin

g a

diffe

rent

pop

ulat

ion.

Spec

ific

IgE,

co

mpo

nent

te

stin

g

Pean

utex

peri

men

tal

tech

niqu

eLi

n et

al,

2012

23Sp

ecifi

c pe

ptid

es A

ra h

2_1

0, A

ra h

2_1

8, A

ra h

1_1

6, a

nd

Ara

h 3

_140

had

90%

sen

sitiv

ity a

nd 9

5% s

peci

ficity

.T

his

stud

y us

ed a

nov

el a

ppro

ach

to t

he d

iagn

osis

of

pea

nut

alle

rgy

but

is n

ot y

et r

eady

for

clin

ical

ap

plic

atio

n.Sp

ecifi

c Ig

E,

com

pone

nt

test

ing

Pean

utC

ross

- se

ctio

nal

Asa

rnoj

et

al,

2012

2189

.5%

of c

hild

ren

who

wer

e A

ra h

8 r

eact

ive

coul

d sa

fely

co

nsum

e pe

anut

.M

ost c

hild

ren

who

wer

e A

ra h

8-p

ositi

ve a

nd r

eact

ed

had

mild

rea

ctio

ns, t

houg

h so

me

had

syst

emic

rea

ctio

ns.

Spec

ific

IgE,

co

mpo

nent

te

stin

g

Pean

utC

ross

- se

ctio

nal

elle

r an

d Bi

ndsl

ev-

Jens

en, 2

013

20Be

st c

orre

latio

n be

twee

n ig

e an

d cl

inic

al t

hres

hold

s w

as

with

usi

ng A

ra h

2 le

vels

>1.

63 k

UA

/L w

hich

had

a s

peci

ficity

of

100

% a

nd s

ensi

tivity

of 7

0%.

Ara

h 2

may

be

help

ful i

n di

stin

guis

hing

bet

wee

n pe

anut

alle

rgy

and

sens

itiza

tion.

Spec

ific

IgE,

co

mpo

nent

te

stin

g

Pean

utC

ross

- se

ctio

nal

Lieb

erm

an e

t al

, 20

1319

ige

to p

eanu

t (.

0.35

kU

A/L

) w

as t

he m

ost

sens

itive

tes

t

(93%

) fo

r pr

edic

ting

resu

lts o

f OFC

. Ara

h 2

was

mos

t

spec

ific

(92%

) an

d ha

d th

e be

st P

PV (

94%

).

Thi

s st

udy

used

pat

ient

s fr

om t

hree

site

s, s

ome

of

who

m w

ere

on o

ral i

mm

unot

hera

py fo

r pe

anut

.

(Con

tinue

d)

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144

O’Keefe et al

Tab

le 1

(Co

ntin

ued)

Mod

alit

yA

llerg

enT

ype

of

stud

yA

utho

rs,

publ

icat

ion

year

Ref

eren

ceFi

ndin

gsC

omm

ents

Saliv

ary

sp

ecifi

c Ig

APe

anut

Pros

pect

ive

co

hort

Kul

is e

t al

, 201

224

Saliv

ary

pean

ut-s

peci

fic Ig

A in

crea

sed

in p

atie

nts

rece

ivin

g

SLIT

com

pare

d to

con

trol

s, b

ut d

id n

ot c

hang

e si

gnifi

cant

ly

over

a 1

2-m

onth

per

iod

of t

reat

men

t.

Incr

ease

d le

vels

of s

aliv

ary

pean

ut-s

peci

fic Ig

A a

re

indu

ced

by t

he S

LiT

inte

rven

tion

alth

ough

it is

not

cl

ear

if it

mig

ht s

erve

to

pred

ict

effe

ctiv

enes

s of

SLi

T.

Spec

ific

IgE,

co

mpo

nent

te

stin

g

egg

Ret

rosp

ectiv

e

coho

rtM

onte

sino

s et

al,

20

1025

Egg

whi

te-s

peci

fic Ig

E of

1.5

2, 1

.35,

and

2.5

9 kU

A/L

pre

dict

ed

reac

tivity

in p

atie

nts

aged

2–3

, 3–4

, and

4–5

yea

rs,

resp

ectiv

ely.

Ret

rosp

ectiv

e st

udy

findi

ng t

hat

child

ren

who

ou

tgro

w e

gg a

llerg

y ha

d si

gnifi

cant

ly lo

wer

spe

cific

IgE

to e

gg w

hite

, Ov

A, a

nd O

vM

.Sp

ecifi

c Ig

E,

com

pone

nt

test

ing

egg

Cro

ss-

sect

iona

lA

less

andr

i et

al,

2012

2794

% o

f Gal

d 1

-neg

ativ

e pa

tient

s to

lera

ted

boile

d eg

g an

d

95%

of G

al d

1-p

ositi

ve p

atie

nts

reac

ted

to r

aw e

gg.

Gal

d 1

ige

reac

tivity

is a

goo

d pr

edic

tor

of c

linic

al

egg

alle

rgy.

Thi

s st

udy

does

not

dis

cuss

bak

ed e

gg

vers

us b

oile

d eg

g.Sp

ecifi

c Ig

E,

com

pone

nt

test

ing

egg

Cro

ss-

sect

iona

lC

aube

t et

al,

2012

26in

chi

ldre

n w

ho w

ere

alle

rgic

to

both

raw

and

bak

ed e

gg

ther

e w

ere

high

er r

atio

s of

spe

cific

IgE/

IgG

for

OV

A a

nd

Ov

M a

ntig

ens

com

pare

d to

chi

ldre

n w

ho c

ould

tol

erat

e

bake

d eg

g. ig

G4 l

evel

s th

emse

lves

did

not

diff

er s

igni

fican

tly

betw

een

the

two

grou

ps.

ige/

igG

4 rat

io m

ay b

e us

eful

in d

iagn

osis

of b

aked

egg

-to

lera

nt c

hild

ren.

Spec

ific

IgE,

SP

TSe

sam

eC

ross

- se

ctio

nal

Perm

aul e

t al

, 20

0928

Spec

ific

IgE

.7

kUA

/L w

as .

90%

spe

cific

. SPT

whe

al d

iam

eter

of

.6

mm

was

.90

% s

peci

fic.

Thi

s st

udy

offe

rs S

PT a

nd s

peci

fic Ig

E va

lues

to

help

pr

edic

t th

e lik

elih

ood

of p

ositi

ve r

eact

ion

in O

FC t

o se

sam

e.Sp

ecifi

c Ig

Ew

heat

an

d so

yC

ross

- se

ctio

nal

Kom

ata

et a

l,

2009

29M

edia

n sp

ecifi

c Ig

E in

whe

at-a

llerg

ic c

hild

ren

was

4.3

1 kU

A/L

, an

d in

soy

bean

-alle

rgic

chi

ldre

n 3.

89 k

UA

/L.

Incr

easi

ng le

vels

of s

peci

fic Ig

E ar

e as

soci

ated

with

in

crea

sed

risk

of f

aile

d O

FC in

whe

at-

and

soyb

ean-

alle

rgic

pat

ient

s. In

whe

at a

llerg

y, a

ge in

fluen

ces

this

re

latio

nshi

p, w

ith y

oung

er c

hild

ren

bein

g m

ore

likel

y to

rea

ct w

hen

spec

ific

IgE

leve

ls w

ere

low

.O

FCM

ilkC

ross

- se

ctio

nal

Cor

rea

et a

l, 20

1011

1O

FC in

Bra

zilia

n ch

ildre

n on

a m

ilk-fr

ee d

iet

to a

sses

s fo

r

imm

edia

te a

nd d

elay

ed r

eact

ions

(up

to

30 d

ays)

. 23.

1% o

f pa

tient

s ha

d a

posi

tive

chal

leng

e.

Thi

s st

udy

did

not

asse

ss ig

e-m

edia

ted

illne

ss. T

hose

w

ith a

his

tory

of a

naph

ylax

is w

ere

excl

uded

from

the

st

udy.

OFC

Milk

Pros

pect

ive

co

hort

Men

donç

a et

al,

20

1237

46 c

hild

ren

with

a c

linic

al h

isto

ry o

f rea

ctio

n to

milk

and

a

posi

tive

SPT

res

pons

e un

derw

ent

chal

leng

e. C

halle

nge

w

as p

ositi

ve in

41.

3%. C

utan

eous

sym

ptom

s w

ere

the

mos

t

com

mon

(73

.7%

), fo

llow

ed b

y re

spir

ator

y (5

7.9%

) an

d

gast

roin

test

inal

(36

.8%

). R

eact

ions

wer

e cl

assi

fied

as m

ild

(57.

9%),

mod

erat

e (3

6.8%

), or

sev

ere

(5.3

%).

epin

ephr

ine

w

as n

ot u

sed

in a

ny o

f the

pat

ient

s.

OFC

is s

afe

and

effe

ctiv

e in

est

ablis

hing

the

dia

gnos

is

of m

ilk a

llerg

y.

SPT

, spe

cific

ig

e, O

FCM

ilk

(bak

ed)

Ret

rosp

ectiv

e

char

t re

view

Bart

nika

s et

al,

20

1239

Am

ong

35 b

aked

milk

cha

lleng

es, 8

3% p

asse

d. O

f the

six

who

fa

iled,

50%

pas

sed

the

initi

al c

halle

nge

but

deve

lope

d sy

mpt

oms

at

hom

e w

ith o

ngoi

ng e

xpos

ure.

Chi

ldre

n w

ith a

n SP

T w

heal

di

amet

er o

f ,12

mm

wer

e 90

% li

kely

to

pass

the

bak

ed m

ilk

chal

leng

e. N

o ch

ild w

ith w

heal

dia

met

er o

f ,7

mm

faile

d th

e ba

ked

milk

cha

lleng

e.

Mos

t m

ilk-a

llerg

ic c

hild

ren

tole

rate

bak

ed m

ilk. S

ome

child

ren

who

initi

ally

pas

s th

e ba

ked

milk

cha

lleng

e m

ay d

evel

op s

ympt

oms

with

ong

oing

exp

osur

e

at h

ome.

Journal of Asthma and Allergy 2014:7 submit your manuscript | www.dovepress.com

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145

Optimal diagnosis and management of food allergies

OFC

Milk

Pros

pect

ive

co

hort

Dam

bach

er e

t al

, 20

1338

116

part

icip

ants

und

erw

ent

OFC

for

milk

. in

66%

, dia

gnos

is

of m

ilk a

llerg

y w

as r

ejec

ted.

Of t

he r

emai

ning

pat

ient

s, 3

2%

had

an a

cute

rea

ctio

n, 3

9% h

ad a

late

rea

ctio

n, a

nd 2

9% h

ad

both

rea

ctio

ns. i

nfan

ts h

ad a

hig

her

min

imum

elic

iting

dos

e

than

old

er c

hild

ren.

OFC

is im

port

ant

in e

stab

lishi

ng t

he d

iagn

osis

of m

ilk

alle

rgy

and

help

s to

avo

id u

nnec

essa

ry e

limin

atio

n di

ets.

OFC

Milk

, egg

, pe

anut

Ret

rosp

ectiv

e

char

t re

view

Mud

d et

al,

2009

112

41%

of p

atie

nts

who

faile

d th

eir

initi

al O

FC t

o m

ilk, p

eanu

t,

or e

gg p

asse

d a

subs

eque

nt c

halle

nge

to t

he s

ame

food

. Se

vere

rea

ctio

n w

ith t

he in

itial

cha

lleng

e w

as a

pre

dict

or o

f fa

ilure

of s

ubse

quen

t ch

alle

nge

with

milk

.

As

a re

tros

pect

ive

char

t re

view

, the

re m

ay b

e se

vera

l un

cont

rolle

d fa

ctor

s.

OFC

Milk

, egg

, co

d, s

oy,

whe

at

Cro

ss-

sect

iona

lw

inbe

rg e

t al

, 20

1344

val

idat

ion

stud

y of

rec

ipes

use

d in

DBP

CFC

for

milk

, egg

, so

y, c

od, a

nd w

heat

. 275

chi

ldre

n ag

ed 8

–10

or 1

4–15

yea

rs

coul

d no

t de

tect

any

sen

sori

al d

iffer

ence

s be

twee

n th

e

activ

e cu

lpri

t fo

od a

nd p

lace

bo fo

r an

y of

the

cha

lleng

e fo

ods.

Prov

ides

a r

ange

of v

alid

ated

rec

ipes

for

DBP

CFC

for

seve

ral f

oods

tha

t ar

e ea

sy t

o pr

epar

e an

d us

e th

e sa

me

liqui

d te

st v

ehic

le.

OFC

egg

Pros

pect

ive

coho

rtes

cude

ro e

t al

, 20

1343

Cha

lleng

ed e

gg-a

llerg

ic p

atie

nts

to b

oth

drie

d eg

g w

hite

and

ra

w e

gg w

hite

. 25%

of p

atie

nts

reac

ted

to b

oth

drie

d eg

g

whi

te a

nd r

aw e

gg w

hite

. 75%

did

not

rea

ct t

o ei

ther

.

Dri

ed e

gg w

hite

is s

uita

ble

for

use

in O

FC a

nd h

as

som

e ad

vant

ages

ove

r ra

w e

gg.

OFC

Pean

utPr

ospe

ctiv

e

coho

rtG

laum

ann

et a

l,

2013

36To

eva

luat

e th

e re

prod

ucib

ility

of O

FC, 2

7 pe

anut

-alle

rgic

pa

tient

s un

derw

ent a

DBP

CFC

follo

wed

by

a sin

gle-

blin

d O

FC.

A n

ovel

test

, bas

ophi

l alle

rgen

thre

shol

d se

nsiti

vity

(CD

-sen

s),

eval

uatin

g ba

soph

il al

lerg

en th

resh

old

sens

itivi

ty, w

as a

lso u

sed.

48

% d

id n

ot r

eact

to e

ither

cha

lleng

e; 5

2% r

eact

ed a

t bot

h.

CD

-sen

s te

stin

g w

as n

ot r

epro

duci

ble.

OFC

s ar

e 10

0% r

epro

duci

ble

for

both

neg

ativ

e an

d po

sitiv

e te

sts.

Pea

nut

alle

rgen

sen

sitiv

ity t

hres

hold

w

as n

ot r

epro

duci

ble

usin

g th

e C

D-s

ens

test

.

OFC

Ret

rosp

ectiv

e

char

t re

view

Lieb

erm

an e

t al

, 20

1134

701

OFC

s pe

rfor

med

in 5

21 p

atie

nts.

Rea

ctio

ns w

ere

el

icite

d in

132

(18

.8%

) ca

ses.

1.7

% o

f the

rea

ctio

ns

requ

ired

tre

atm

ent

with

epi

neph

rine

.

OFC

per

form

ed in

an

outp

atie

nt s

ettin

g un

der

appr

opri

ate

supe

rvis

ion

is s

afe.

it is

an

impo

rtan

t st

ep in

est

ablis

hing

the

dia

gnos

is o

f foo

d al

lerg

y an

d av

oidi

ng u

nnec

essa

ry e

limin

atio

n di

ets.

OFC

Ret

rosp

ectiv

e

char

t re

view

Flei

sche

r et

al,

20

1132

Follo

win

g O

FCs

in c

hild

ren

with

elim

inat

ion

diet

s ba

sed

on

imm

unoa

ssay

s, 8

4%–9

3% w

ere

able

to

rein

trod

uce

fo

ods

they

had

bee

n av

oidi

ng.

Thi

s st

udy

exam

ined

a p

opul

atio

n of

chi

ldre

n re

ferr

ed

to a

spe

cial

ized

car

e ce

ntre

. OFC

is a

n es

sent

ial

elem

ent

in t

he d

iagn

osis

of f

ood

alle

rgy.

Rel

ying

so

lely

on

imm

unoa

ssay

s ca

n re

sult

in u

nnec

essa

ry

elim

inat

ion

diet

s.O

FCR

etro

spec

tive

ch

art

revi

ewC

alva

ni e

t al

, 201

235

Of 5

44 O

FCs

anal

yzed

, 48.

3% w

ere

posi

tive,

of w

hich

65.

7%

wer

e m

ild. 3

1.9%

of t

hose

who

rea

cted

had

mul

tiorg

an

invo

lvem

ent,

and

2.4%

had

ana

phyl

axis

. Ant

ihis

tam

ines

w

ere

the

mos

t co

mm

only

use

d tr

eatm

ent

duri

ng c

halle

nge.

OFC

s ar

e sa

fe w

hen

perf

orm

ed b

y an

alle

rgis

t in

the

ap

prop

riat

e se

ttin

g.

OFC

Rev

iew

Järv

inen

and

Si

cher

er, 2

012

33Fo

od-s

peci

fic Ig

E te

sts

are

help

ful b

iom

arke

rs o

f alle

rgy,

but

la

ck s

ensi

tivity

and

spe

cific

ity. O

FC r

emai

ns t

he s

tand

ard

fo

r di

agno

sis

of r

eact

ivity

. ige

tes

ting

does

not

ass

ess

for

no

n-ig

e-m

edia

ted

reac

tions

.

Rev

iew

art

icle

pro

vidi

ng a

n ov

ervi

ew o

n te

chni

que

and

inte

rpre

tatio

n of

OFC

s.

OFC

Rev

iew

Ase

ro e

t al

, 200

94

whi

le D

BPC

FC is

the

gol

d st

anda

rd fo

r di

agno

sis

of fo

od

alle

rgy,

it is

clin

ical

ly c

umbe

rsom

e an

d di

fficu

lt to

per

form

. O

pen

chal

leng

es h

ave

few

er d

isad

vant

ages

.

Dis

cret

ion

is n

eede

d w

hen

deci

ding

whe

ther

a p

atie

nt

need

s a

food

cha

lleng

e, a

nd w

heth

er it

sho

uld

be

DBP

CFC

or

open

.

(Con

tinue

d)

Journal of Asthma and Allergy 2014:7submit your manuscript | www.dovepress.com

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146

O’Keefe et al

Tab

le 1

(Co

ntin

ued)

Mod

alit

yA

llerg

enT

ype

of

stud

yA

utho

rs,

publ

icat

ion

year

Ref

eren

ceFi

ndin

gsC

omm

ents

OFC

Pros

pect

ive

co

hort

van

der

vel

de

et a

l, 20

1241

Hea

lth-r

elat

ed Q

OL

scor

es im

prov

ed a

fter

DBP

CFC

, with

gr

eate

r im

prov

emen

t af

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nega

tive

chal

leng

e th

an p

ositi

ve

chal

leng

e. T

here

was

long

itudi

nal v

alid

ity o

f the

Foo

d A

llerg

y

Qua

lity

of L

ife Q

uest

ionn

aire

.

whe

n in

dica

ted,

OFC

sho

uld

be p

erfo

rmed

, as

hea

lth-r

elat

ed Q

OL

impr

oves

follo

win

g th

is

asse

ssm

ent.

OFC

Pean

ut,

tree

nut

sPr

ospe

ctiv

e

coho

rtK

nibb

et

al, 2

012

4240

pat

ient

s an

d th

eir

mot

hers

com

plet

ed q

uest

ionn

aire

s

befo

re a

nd 3

–6 m

onth

s af

ter

OFC

. Bot

h pa

rent

and

chi

ld

expe

rien

ced

impr

oved

food

-rel

ated

QO

L af

ter

chal

leng

e.

Patie

nt a

nxie

ty le

vels

wer

e de

crea

sed

afte

r ch

alle

nge,

whi

le

pare

ntal

anx

iety

rem

aine

d th

e sa

me.

impr

ovem

ent

was

in

depe

nden

t of

cha

lleng

e ou

tcom

e, d

espi

te c

oexi

stin

g

food

alle

rgie

s in

50%

of c

hild

ren.

OFC

is a

ssoc

iate

d w

ith in

crea

sed

pare

ntal

anx

iety

on

the

day

of t

he c

halle

nge

but

lead

s to

impr

oved

QO

L an

d de

crea

sed

patie

nt a

nxie

ty fo

llow

ing

chal

leng

e.

OFC

Cro

ss-

sect

iona

lin

dinn

imeo

et

al,

2013

40R

epor

ted

QO

L w

as w

orse

am

ong

thos

e w

ith a

his

tory

of

anap

hyla

xis

and

aged

.3

year

s. D

urat

ion

of e

xclu

sion

die

t

had

a si

gnifi

cant

impa

ct o

n Q

OL

for

milk

-alle

rgic

chi

ldre

n

but

not

child

ren

with

oth

er fo

od a

llerg

ies.

elim

inat

ion

diet

s ne

gativ

ely

impa

ct Q

OL.

The

y m

ust

only

be

empl

oyed

whe

n ne

cess

ary

and

for

the

shor

test

dur

atio

n po

ssib

le.

Gut

tryp

tase

Cro

ss-

sect

iona

lH

agel

et

al, 2

013

113

Patie

nts

with

gas

troi

ntes

tinal

sym

ptom

s of

food

alle

rgy

ha

d el

evat

ed le

vels

of t

rypt

ase

in g

ut m

ucos

a co

mpa

red

to

con

trol

s.

Nov

el a

ppro

ach

in in

vest

igatio

n of

food

alle

rgy,

but

cl

inic

al re

leva

nce

and

appl

icat

ion

may

not

war

rant

its

use.

Spec

ific

IgG

Cro

ss-

sect

iona

lZ

eng

et a

l, 20

1330

Food

-spe

cific

IgG

is v

aria

ble

in s

ympt

omat

ic a

nd h

ealth

y

Chi

nese

adu

lts.

Spec

ific

IgG

is n

ot a

rel

iabl

e m

eans

of d

iagn

osin

g fo

od

alle

rgy.

Abb

revi

atio

ns: D

BPC

FC, d

oubl

e-bl

ind,

pla

cebo

-con

trol

led

food

cha

lleng

e; ig

A, i

mm

unog

lobu

lin A

; ige

, im

mun

oglo

bulin

e; i

gG4,

imm

unog

lobu

lin G

, typ

e 4;

NPv

, neg

ativ

e pr

edic

tive

valu

e; O

FC, o

pen

food

cha

lleng

e; O

vA

, ova

lbum

in;

Ov

M, o

vom

ucoi

d; P

Pv, p

ositi

ve p

redi

ctiv

e va

lue;

QO

L, q

ualit

y of

life

; SLi

T, s

ublin

gual

imm

unot

hera

py; S

PT, s

kin

pric

k te

st.

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147

Optimal diagnosis and management of food allergies

Tab

le 2

Man

agem

ent

of fo

od a

llerg

y

Mod

alit

yA

llerg

enT

ype

of

stud

yA

utho

rs,

publ

icat

ion

year

Ref

eren

ceFi

ndin

gsC

omm

ents

Prev

entio

n

in p

regn

ancy

Pean

utR

etro

spec

tive

Sich

erer

et

al,

2010

46in

a c

ohor

t of

infa

nts

with

like

ly m

ilk o

r eg

g al

lerg

y, fr

eque

nt

pean

ut c

onsu

mpt

ion

(OR

2.9)

, ige

leve

ls to

milk

and

egg

, mal

e se

x,

and

non-

whi

te r

ace

wer

e as

soci

ated

with

pea

nut-

sige

.5

kUA

/L.

Mat

erna

l pea

nut

cons

umpt

ion

duri

ng p

regn

ancy

m

ay b

e as

soci

ated

with

sen

sitiz

atio

n of

infa

nts,

al

thou

gh a

llerg

y w

as n

ot e

valu

ated

.Pr

even

tion

in

pre

gnan

cyPe

anut

Ret

rosp

ectiv

eD

esR

oche

s et

al,

20

1048

Mot

hers

of p

eanu

t-al

lerg

ic c

hild

ren

repo

rted

hig

her

co

nsum

ptio

n of

pea

nut

duri

ng p

regn

ancy

and

bre

astfe

edin

g

(OR

4.2

2, 1

.57–

11.3

0 [9

5% C

i]; 0

.28,

1.3

1–3.

97 [

95%

Ci])

.

Rec

all b

ias

may

hav

e in

fluen

ced

the

resu

lts o

f thi

s st

udy.

Prev

entio

n

in p

regn

ancy

RC

Tw

est

et a

l, 20

1251

Hig

her

mat

erna

l vita

min

C in

take

sho

wed

a t

rend

tow

ard

a

redu

ced

asso

ciat

ion

with

whe

eze,

alth

ough

it w

as n

ot

stat

istic

ally

sig

nific

ant

(P=0

.06)

. inc

reas

ed m

ater

nal c

oppe

r

inta

ke w

as a

ssoc

iate

d w

ith r

educ

ed r

isk

of w

heez

e an

d

ecze

ma,

but

not

food

alle

rgy.

Mat

erna

l ant

ioxi

dant

inta

ke m

ay in

fluen

ce t

he

deve

lopm

ent

of a

llerg

ic d

isea

se in

chi

ldre

n.

Part

icul

arly

, inc

reas

ed d

ieta

ry c

oppe

r m

ay r

educ

e w

heez

e an

d ec

zem

a at

1 y

ear.

The

re w

as n

o si

gnifi

cant

effe

ct o

n fo

od a

llerg

y.Pr

even

tion

in

pre

gnan

cyR

CT

Palm

er e

t al

, 201

252

No

signi

fican

t diff

eren

ce a

t age

1 y

ear

betw

een

child

ren

of

mot

hers

who

wer

e su

pple

men

ted

with

pol

yuns

atur

ated

fatt

y

acid

s du

ring

preg

nanc

y an

d co

ntro

ls.

Poly

unsa

tura

ted

fatt

y ac

id s

uppl

emen

tatio

n du

ring

pr

egna

ncy

does

not

red

uce

the

risk

of a

llerg

ic

dise

ase

in c

hild

hood

.Pr

even

tion

in

pre

gnan

cyPe

anut

, tr

ee n

uts,

se

sam

e

Cro

ss-

sect

iona

lH

su e

t al

, 201

347

Mat

erna

l con

sum

ptio

n of

tree

nut

and

ses

ame

seed

dur

ing

the

fir

st tw

o tr

imes

ters

was

ass

ocia

ted

with

a 6

0% h

ighe

r ris

k of

ha

ving

a c

hild

sen

sitiz

ed to

tree

nut

, pea

nut,

or s

esam

e se

ed.

Chi

ldre

n w

ith a

sthm

a an

d en

viro

nmen

tal a

llerg

ies

had

incr

ease

d

risk

of s

ensit

izat

ion.

Mat

erna

l con

sum

ptio

n of

tre

e nu

t an

d se

sam

e se

ed le

ads

to g

reat

er r

isk

of h

avin

g a

child

who

is

sen

sitiz

ed t

o tr

ee n

ut, p

eanu

t, or

ses

ame

seed

. T

his

stud

y di

d no

t ev

alua

te a

llerg

y to

the

se fo

ods.

Prev

entio

n

in in

fanc

yeg

gC

ross

- se

ctio

nal

Kop

lin e

t al

, 201

059

Com

pare

d w

ith in

trod

uctio

n at

4–6

mon

ths

of a

ge, l

ater

in

trod

uctio

n w

as a

ssoc

iate

d w

ith h

ighe

r ri

sk o

f egg

alle

rgy

(O

R 1

.6 fo

r 10

–12

mon

ths,

3.4

for

.12

mon

ths)

. At

age

4–

6 m

onth

s, fi

rst

expo

sure

to

cook

ed e

gg (

boile

d, s

cram

bled

, fr

ied,

or

poac

hed)

red

uced

the

ris

k of

egg

alle

rgy

com

pare

d to

fir

st e

xpos

ure

to e

gg in

bak

ed g

oods

(eg

g-co

ntai

ning

cak

es o

r

bisc

uits

or

sim

ilar

prod

ucts

) (O

R 0

.2).

Dur

atio

n of

br

east

feed

ing

and

age

of in

trod

uctio

n of

sol

ids

wer

e no

t

asso

ciat

ed w

ith e

gg a

llerg

y.

intr

oduc

tion

of c

ooke

d eg

g be

twee

n 4

and

6

mon

ths

of a

ge m

ay b

e pr

otec

tive.

Opt

imal

tim

ing

of in

trod

uctio

n of

food

s to

indu

ce

tole

ranc

e re

mai

ns u

nder

inve

stig

atio

n.

Prev

entio

n

in in

fanc

yM

ilkPr

ospe

ctiv

e

coho

rtK

atz

et a

l, 20

1058

inci

denc

e of

ige-

med

iate

d m

ilk a

llerg

y w

as 0

.5%

. The

mea

n ag

e

of in

trod

uctio

n of

cow

’s m

ilk w

as d

iffer

ent b

etw

een

heal

thy

in

fant

s (6

1.6

days

) and

milk

-alle

rgic

infa

nts

(116

.1 d

ays)

.

earl

y ex

posu

re t

o co

w’s

milk

may

pro

mot

e to

lera

nce.

Prev

entio

n

in in

fanc

yR

CT

Jens

en e

t al

, 201

253

Hig

h-ri

sk c

hild

ren

rand

omiz

ed t

o re

ceiv

e pr

obio

tics

or

plac

ebo

for

first

6 m

onth

s of

life

. Lon

g-te

rm fo

llow

-up

sh

owed

no

sign

ifica

nt d

iffer

ence

in a

llerg

ic d

isea

se b

etw

een

th

e gr

oups

at

age

5 ye

ars.

earl

y pr

obio

tic s

uppl

emen

tatio

n do

es n

ot r

educ

e th

e ri

sk o

f alle

rgic

dis

ease

in c

hild

hood

.

Prev

entio

n in

in

fanc

yR

CT

D’v

az e

t al

, 201

256

The

re w

as n

o as

soci

atio

n be

twee

n fis

h oi

l sup

plem

enta

tion

an

d al

lerg

ic d

isea

se.

Fish

oil

supp

lem

enta

tion

does

not

pre

vent

ch

ildho

od a

llerg

ic d

isea

se.

(Con

tinue

d)

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148

O’Keefe et al

Tab

le 2

(Co

ntin

ued)

Mod

alit

yA

llerg

enT

ype

of

stud

yA

utho

rs,

publ

icat

ion

year

Ref

eren

ceFi

ndin

gsC

omm

ents

Prev

entio

n

in in

fanc

yC

ase-

cont

rol

Gri

msh

aw e

t al

, 20

1357

infa

nts

diag

nose

d w

ith fo

od a

llerg

y at

2 y

ears

wer

e in

trod

uced

to

sol

ids

earl

ier

(,16

wee

ks) a

nd w

ere

less

like

ly t

o be

re

ceiv

ing

brea

st m

ilk w

hen

cow

’s m

ilk w

as in

trod

uced

.

Opt

imal

tim

ing

for

intr

oduc

tion

of fo

ods

to

indu

ce t

oler

ance

is u

nkno

wn.

Prev

entio

n

in in

fanc

yR

CT

Loo

et a

l, 20

1455

infa

nts

from

bir

th t

o 6

mon

ths

of a

ge r

ecei

ved

cow

’s m

ilk

form

ula

with

or

with

out

prob

iotic

sup

plem

ents

. At

the

age

of

5 y

ears

, the

re w

ere

no s

igni

fican

t di

ffere

nces

bet

wee

n th

e

grou

ps in

the

pro

port

ion

of c

hild

ren

who

dev

elop

ed a

sthm

a,

alle

rgic

rhi

nitis

, ecz

ema,

or fo

od a

llerg

y.

Prob

iotic

sup

plem

enta

tion

duri

ng in

fanc

y do

es n

ot

prot

ect

agai

nst

the

deve

lopm

ent

of a

llerg

ic d

isea

se

in c

hild

hood

.

Prev

entio

n

in in

fanc

yR

CT

wes

t et

al,

2013

5425

% o

f pat

ient

s in

the

pro

biot

ic t

reat

men

t gr

oup

vers

us 3

5%

of c

ontr

ols

had

som

e ty

pe o

f alle

rgic

dis

ease

.Pr

obio

tic s

uppl

emen

tatio

n du

ring

infa

ncy

does

not

pr

otec

t ag

ains

t al

lerg

ic d

isea

se a

t ag

e 8–

9 ye

ars.

Prev

entio

n

in c

hild

hood

Cro

ss-

sect

iona

lD

eMut

h et

al,

20

1360

Chi

ldre

n pr

esen

ting

to a

llerg

y cl

inic

with

a h

istor

y of

par

ent-

re

port

ed a

ntac

id u

se h

ad a

hig

her

prev

alen

ce o

f foo

d al

lerg

y

(57%

) com

pare

d to

con

trol

s (3

2%).

Patie

nts

who

had

take

n

anta

cids

also

had

hig

her

mea

n pe

anut

-sig

e le

vels

than

con

trol

s

(11.

0 ±

5.0

kUA

/L v

ersu

s 2.

0 ±

5.5

kUA

/L; P

= 0.

01)

in a

coh

ort

of c

hild

ren

pres

entin

g to

alle

rgy

clin

ic,

pare

nt-r

epor

ted

anta

cid

use

was

ass

ocia

ted

with

an

incr

ease

d ri

sk o

f foo

d al

lerg

y.

Prev

entio

n –

al

lerg

en

avoi

danc

e

Milk

Cro

ss-

sect

iona

lBo

yano

-Mar

tínez

et

al,

2009

6740

% o

f chi

ldre

n w

ith m

ilk a

llerg

y ha

d ac

cide

ntal

exp

osur

e

resu

lting

in a

llerg

ic r

eact

ions

: 53%

mild

, 32%

mod

erat

e,

15%

sev

ere.

Acc

iden

tal e

xpos

ures

to

milk

in m

ilk-a

llerg

ic

child

ren

are

com

mon

.

Prev

entio

n –

al

lerg

en

avoi

danc

e

Milk

Pros

pect

ive

coho

rtT

uokk

ola

et a

l,

2010

6685

% o

f fam

ilies

adh

ered

to

the

milk

-elim

inat

ion

diet

. Old

er

child

ren

and

thos

e w

ho w

ere

mon

o-se

nsiti

zed

wer

e m

ore

lik

ely

to h

ave

som

e m

ilk in

the

ir d

iet.

it is

unc

lear

whe

ther

the

chi

ldre

n in

the

stu

dy

wer

e av

oidi

ng m

ilk fo

r ig

e-m

edia

ted

alle

rgy

or

into

lera

nce.

The

par

ticip

ants

in t

he s

tudy

wer

e re

ceiv

ing

spec

ial i

nfan

t fo

rmul

a re

imbu

rsem

ent,

so t

his

may

par

tially

acc

ount

for

the

high

rat

e of

ad

here

nce.

Prev

entio

n –

al

lerg

en

avoi

danc

e

Milk

(co

w

vers

us

cam

el)

Pros

pect

ive

coho

rteh

laye

l et

al, 2

011

6880

% o

f cow

’s m

ilk-a

llerg

ic c

hild

ren

had

a ne

gativ

e SP

T

resp

onse

to

cam

el m

ilk a

nd c

ould

saf

ely

inge

st it

. Chi

ldre

n

with

a p

ositi

ve S

PT r

espo

nse

to c

amel

milk

wer

e no

t

chal

leng

ed.

Patie

nts

in t

his

stud

y w

ere

not

chal

leng

ed t

o co

w’s

milk

to

confi

rm a

llerg

y; it

is p

ossi

ble

they

ac

quir

ed t

oler

ance

. Cam

el m

ilk c

ould

be

a sa

fe

alte

rnat

ive

to c

ow’s

milk

, but

thi

s m

ay n

ot b

e pr

actic

al d

epen

ding

on

cultu

ral i

nflue

nces

.Pr

even

tion

–

alle

rgen

av

oida

nce

Cro

ss-

sect

iona

lSa

kella

riou

et

al,

2010

71Th

e pe

rcen

tage

of p

eopl

e ab

le t

o co

rrec

tly id

entif

y m

ore

than

50

% o

f the

ter

ms

asso

ciat

ed w

ith a

giv

en a

llerg

en w

ere:

4.8%

of

the

gen

eral

pop

ulat

ion,

2.9

% o

f par

ents

of f

ood-

alle

rgic

ch

ildre

n, a

nd 3

9.5%

of h

ealth

car

e pr

ofes

siona

ls w

ithou

t a

hi

stor

y of

food

alle

rgy.

Fem

ales

, tho

se w

ith h

ighe

r ed

ucat

ion,

an

d th

ose

with

a h

istor

y of

food

alle

rgy

scor

ed m

ore

high

ly.

Con

sum

er c

onfu

sion

reg

ardi

ng la

belin

g fo

r fo

od

alle

rgie

s is

pre

vale

nt. L

abel

ing

mus

t st

ate

exac

t te

rms

for

each

alle

rgen

, and

“m

ay c

onta

in”

stat

emen

ts s

houl

d be

lim

ited

to a

void

mis

lead

ing

labe

ls.

Prev

entio

n –

al

lerg

en

avoi

danc

e

Rev

iew

Tur

ner

et a

l, 20

1173

A r

evie

w o

f foo

d-la

belin

g pr

actic

es d

etai

ling

both

the

co

nsum

ers’

and

man

ufac

ture

rs’ p

ersp

ectiv

es. O

verl

y

stri

ngen

t la

belin

g m

easu

res

redu

ce o

ptio

ns fo

r al

lerg

ic

indi

vidu

als,

lead

ing

to a

nxie

ty a

nd a

ffect

ing

QO

L.

The

cur

rent

sys

tem

of f

ood

labe

ling

is n

ot

bene

ficia

l for

man

ufac

ture

rs, c

onsu

mer

s, o

r he

alth

pr

ofes

sion

als.

A s

tand

ardi

zed

risk

ass

essm

ent

tool

su

ch a

s v

iTA

L co

uld

help

impr

ove

food

-labe

ling

prac

tices

.

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149

Optimal diagnosis and management of food allergies

Prev

entio

n –

al

lerg

en

avoi

danc

e

Seaf

ood

Cro

ss-

sect

iona

lN

g et

al,

2011

6525

% o

f sea

food

-alle

rgic

pat

ient

s se

en in

alle

rgy

clin

ic w

ere

un

able

to r

ecal

l die

tary

adv

ice

prov

ided

. Non

ethe

less

89%

of

all p

aren

ts im

plem

ente

d a

safe

die

t, bu

t ove

r ha

lf of

the

89%

fo

llow

ed a

mor

e st

ringe

nt e

limin

atio

n di

et th

an n

eede

d. 1

/5

had

alle

rgic

rea

ctio

ns to

sea

food

afte

r di

agno

sis. P

resc

riptio

n

of a

n eA

i was

ass

ocia

ted

with

impr

oved

adh

eren

ce.

Food

alle

rgy

has

a de

trim

enta

l effe

ct o

n Q

OL.

M

any

pare

nts

have

diffi

culty

rec

allin

g di

etar

y ad

vice

giv

en a

nd im

plem

ent

mor

e st

ring

ent

diet

s th

an n

eces

sary

.

Prev

entio

n –

al

lerg

en

avoi

danc

e

Pros

pect

ive

coho

rtPu

lcin

i et

al, 2

011

74A

sur

vey

of M

issi

ssip

pi, U

SA p

ublic

sch

ool n

urse

s fo

und

that

97

% o

f sch

ools

had

at

leas

t on

e fo

od-a

llerg

ic s

tude

nt. 3

0% o

f sc

hool

s ha

d fo

od a

llerg

y ac

tion

plan

s. A

ctio

n pl

ans

wer

e m

ore

lik

ely

to e

xist

whe

n th

e nu

rse

had

rece

ived

info

rmat

ion

from

a

phys

icia

n.

Mos

t sc

hool

s ha

ve fo

od-a

llerg

ic s

tude

nts,

but

re

lativ

ely

few

hav

e ac

tion

plan

s fo

r th

ese

stud

ents

.

Prev

entio

n –

al

lerg

en

avoi

danc

e

Cro

ss-

sect

iona

lBe

n-Sh

osha

n et

al,

2012

72Pr

ecau

tiona

ry s

tate

men

t “n

ot s

uita

ble”

was

mos

t ef

fect

ive

in

dete

rrin

g pu

rcha

se o

f a p

rodu

ct. i

ndiv

idua

ls d

irec

tly a

ffect

ed

by fo

od a

llerg

y w

ere

mor

e lik

ely

to a

void

pro

duct

s w

ith

“may

con

tain

”, “

may

be

proc

esse

d on

the

sam

e eq

uipm

ent

as

pro

duct

s co

ntai

ning

”, a

nd “

not

suita

ble

for”

on

the

labe

l th

an in

dire

ctly

affe

cted

sub

ject

s. H

ouse

hold

s re

port

ing

a

mod

erat

e/se

vere

alle

rgy

wer

e m

ore

likel

y to

avo

id.

The

effe

ct o

f lab

elin

g on

alle

rgic

pat

ient

s is

co

mpl

ex a

nd m

ultif

acto

rial

. A s

tand

ardi

zed

labe

ling

proc

ess

with

few

er v

aria

tions

may

be

hel

pful

for

cons

umer

s in

iden

tifyi

ng w

hich

pr

oduc

ts t

o av

oid.

Prev

entio

n –

al

lerg

en

avoi

danc

e

Cro

ss-

sect

iona

lK

im e

t al

, 201

275

71%

of s

choo

ls in

Kor

ea r

elie

d on

par

enta

l rep

orts

of f

ood

al

lerg

y. 4

7% o

f par

ticip

atin

g sc

hool

s ha

d ex

perie

nced

stu

dent

vi

sits

to a

sch

ool h

ealth

roo

m d

ue to

food

alle

rgy

with

in th

e

prev

ious

yea

r. .

80%

rel

ied

on s

elf-c

are

with

out s

choo

l-wid

e

mea

sure

s fo

r fo

od a

llerg

ies.

in K

orea

, mos

t sc

hool

s do

not

hav

e a

plan

for

man

agin

g fo

od a

llerg

ies

amon

g st

uden

ts. T

he

auth

ors

sugg

est

that

suc

h pl

ans

be im

plem

ente

d.

Prev

entio

n –

al

lerg

en

avoi

danc

e

Cro

ss-

sect

iona

ler

can

et a

l, 20

1276

52%

of t

each

ers

knew

whi

ch o

f the

ir s

tude

nts

had

alle

rgic

di

seas

e. P

olle

n w

as t

houg

ht t

o be

the

mos

t co

mm

on a

gent

to

cau

se a

naph

ylax

is (

54%

), fo

llow

ed b

y fo

od (

47%

). A

mon

g

food

s, e

gg (

30.4

%)

and

stra

wbe

rrie

s (2

5.3%

) w

ere

thou

ght

to

be

the

two

lead

ing

caus

es. O

nly

10%

wer

e aw

are

of a

n

eAi,

and

4% k

new

whe

re t

o ap

ply

it. 2

5% o

f tea

cher

s kn

ew

all o

f the

sym

ptom

s of

ana

phyl

axis

and

6%

rep

orte

d th

ere

w

as a

man

agem

ent

plan

for

anap

hyla

xis

in t

he s

choo

l.

Prim

ary

scho

ol t

each

ers

are

not

wel

l inf

orm

ed

abou

t fo

od a

llerg

y an

d an

aphy

laxi

s. T

rain

ing

prog

ram

s on

the

sub

ject

sho

uld

be im

plem

ente

d.

Prev

entio

n –

al

lerg

en

avoi

danc

e

Milk

Cro

ss-

sect

iona

lBe

rni C

anan

i et

al,

2013

114

exam

ined

new

am

ino

acid

form

ula

in 6

0 pa

tient

s w

ith ig

e or

no

n-ig

e-m

edia

ted

reac

tion

to m

ilk. N

o pa

tient

s ha

d im

med

iate

or

del

ayed

rea

ctio

ns. F

ecal

con

cent

ratio

n of

cal

prot

ectin

and

eo

sinop

hil c

atio

nic

prot

ein

rem

aine

d st

able

afte

r ex

posu

re t

o

the

new

am

ino

acid

form

ula.

Prov

ides

a s

afe

amin

o ac

id fo

rmul

a al

tern

ativ

e fo

r ch

ildre

n w

ith ig

e- a

nd n

on-ig

e-m

edia

ted

reac

tions

to

cow

’s m

ilk.

Prev

entio

n –

al

lerg

en

avoi

danc

e

Pros

pect

ive

co

hort

Zur

zolo

et

al,

2013

7065

% o

f pro

duct

s ha

d w

arni

ng la

bels

for

an a

llerg

en t

hat

was

no

t lis

ted

in t

he in

gred

ient

s. M

ost

com

mon

wer

e tr

ee n

uts

(3

6.2%

), fo

llow

ed b

y pe

anut

s (3

4.1%

), se

sam

e (2

7.5%

), an

d

egg

(22.

6%).

“May

con

tain

tra

ces

of”

was

the

mos

t co

mm

on

type

of s

tate

men

t us

ed (

29%

).

The

use

of p

reca

utio

nary

labe

ling

for

food

alle

rgy

is h

igh,

lead

ing

to r

estr

icte

d di

ets

for

cons

umer

s w

ith a

llerg

ies.

(Con

tinue

d)

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150

O’Keefe et al

Tab

le 2

(Co

ntin

ued)

Mod

alit

yA

llerg

enT

ype

of

stud

yA

utho

rs,

publ

icat

ion

year

Ref

eren

ceFi

ndin

gsC

omm

ents

eAi

Tel

epho

ne

surv

eySo

ller

et a

l, 20

1111

5Te

leph

one

surv

ey t

hat

iden

tified

3.2

% o

f par

ticip

ants

as

havi

ng

a pr

obab

le fo

od a

llerg

y. O

f the

se, 4

5% h

ad a

n eA

i. Fa

ctor

s

that

incr

ease

d th

e pr

obab

ility

of h

avin

g an

eA

i wer

e: m

arri

age/

pa

rtne

r, c

hild

ren,

fem

ale,

mul

tiple

food

alle

rgie

s, hi

stor

y of

be

ing

trea

ted

with

epi

neph

rine

, and

con

firm

ator

y te

stin

g.

Hea

lth c

are

prov

ider

s an

d pa

tient

s ne

ed m

ore

educ

atio

n on

the

rec

ogni

tion

and

man

agem

ent

of

anap

hyla

xis.

eAi

Cro

ss-

sect

iona

lD

eMut

h an

d

Fitz

patr

ick,

201

177

59%

had

an

eAi i

n cl

inic

on

follo

w-u

p vi

sit,

of w

hich

79%

re

port

ed h

avin

g re

ceiv

ed t

rain

ing

in it

s us

e. H

avin

g eA

i tr

aini

ng w

as a

ssoc

iate

d w

ith h

avin

g an

eA

i ava

ilabl

e. F

ewer

ch

ildre

n ag

ed .

5 ye

ars

repo

rted

hav

ing

an e

Ai a

t sc

hool

du

ring

lunc

h (2

5%)

than

tho

se ,

5 ye

ars

(42%

).

Man

y ch

ildre

n do

not

hav

e an

eA

i ava

ilabl

e at

all

times

. eA

i tra

inin

g im

prov

es t

he li

kelih

ood

of e

Ai

carr

iage

.

eAi

Cro

ss-

sect

iona

lSe

gal e

t al

, 201

279

eval

uate

d 14

1 pa

tient

s: 9

.9%

had

use

d ep

inep

hrin

e pr

evio

usly

. 37

% h

ad a

val

id d

evic

e w

ith t

hem

at

follo

w-u

p vi

sit.

62%

–87%

in

corr

ectly

per

form

ed s

teps

in u

se o

f an

eAi.

41 p

artic

ipan

ts

wer

e re

eval

uate

d 1

year

late

r, a

fter

whi

ch t

ime

the

mea

n

scor

es im

prov

ed fr

om 4

.71

to 6

.7.

Man

y pa

tient

s do

not

car

ry v

alid

eA

is a

nd a

re

not

skill

ed in

the

ir u

se. R

epea

ted

inst

ruct

ion

may

im

prov

e th

is s

kill.

eAi

Pros

pect

ive

coho

rtSp

ina

et a

l, 20

1278

Ass

esse

d in

fluen

ce o

f per

iodi

c ch

ecks

by

scho

ol n

urse

on

EAI

carr

ying

am

ong

adol

esce

nts.

Peri

odic

che

cks

did

not

influ

ence

th

e ra

te o

f car

ryin

g, b

ut t

hose

who

did

car

ry e

Ais

wer

e m

ore

lik

ely

to h

ave

unex

pire

d m

edic

atio

n w

ith p

erio

dic

rem

inde

rs.

Car

riag

es r

ates

of e

Ais

are

low

am

ong

adol

esce

nts.

we

mus

t w

ork

to d

evel

op e

ffect

ive

inte

rven

tions

to

impr

ove

this

.

eAi

Cro

ss-

sect

iona

lSi

mon

s et

al,

2012

116

Mos

t al

lerg

ists

exp

ect

patie

nts

aged

12–

14 y

ears

to

desc

ribe

an

aphy

laxi

s sy

mpt

oms

(95.

4%),

dem

onst

rate

use

of a

n eA

i (9

3.1%

), ca

rry

an e

Ai (

88.1

%),

lear

n to

sel

f-inj

ect

an e

Ai

(84.

5%)

and

be a

ble

to s

elf-i

njec

t (7

8.6%

).

Mos

t pe

diat

ric

alle

rgis

ts e

xpec

t th

eir

patie

nts

to

be a

ble

to s

elf-a

dmin

iste

r an

eA

i bet

wee

n th

e ag

es

of 1

2 an

d 14

yea

rs. T

here

are

no

patie

nt d

ata

on

optim

al t

imin

g of

tra

nsfe

r of

res

pons

ibili

ty.

eAi

Cro

ss-

sect

iona

lPi

nczo

wer

et

al,

2013

80U

sed

FAQ

OL

to a

sses

s im

pact

of p

resc

ript

ion

of a

n eA

i.

Bein

g ag

ed 7

–12

year

s, h

avin

g fo

ur o

r m

ore

food

alle

rgie

s,

and

hist

ory

of a

naph

ylax

is h

ad s

tron

gest

impa

ct o

n Q

OL.

Pa

tient

s is

sued

an

eAi r

epor

ted

low

er Q

OL.

We

mus

t w

eigh

the

ris

ks a

nd b

enefi

ts o

f pr

escr

ibin

g eA

is a

s th

ey a

re a

ssoc

iate

d w

ith

redu

ced

QO

L.

eAi

Pean

utPr

ospe

ctiv

e

coho

rtC

had

et a

l, 20

138

56%

of p

aren

ts o

f chi

ldre

n w

ith p

eanu

t al

lerg

y ex

pres

sed

fe

ar a

bout

usi

ng e

Ai.

Fear

was

att

ribu

ted

to c

once

rn

abou

t hu

rtin

g th

e ch

ild, u

sing

the

eA

i inc

orre

ctly

, or

a

bad

outc

ome.

Par

ents

of c

hild

ren

with

a h

isto

ry o

f se

vere

rea

ctio

n, lo

ng d

urat

ion

of d

isea

se, o

r w

ho w

ere

sa

tisfie

d w

ith E

AI t

rain

ing

wer

e le

ss li

kely

to

be a

frai

d.

Man

y pa

rent

s of

pea

nut-

alle

rgic

chi

ldre

n ar

e af

raid

to

use

an

eAi.

Pare

nt t

rain

ing

can

help

dec

reas

e fe

ar a

ssoc

iate

d w

ith e

Ais

.

FAH

F-2

RC

Tw

ang

et a

l, 20

1063

Am

ong

18 a

ctiv

e in

terv

entio

n an

d pl

aceb

o su

bjec

ts, t

here

w

ere

no s

igni

fican

t diff

eren

ces

in v

ital s

igns

, phy

sical

ex

amin

atio

n, la

bora

tory

dat

a, p

ulm

onar

y fu

nctio

n te

st

resu

lts, a

nd e

lect

roca

rdio

gram

dat

a ob

tain

ed b

efor

e an

d

afte

r tr

eatm

ent v

isits

.

FAH

F-2

was

saf

e an

d w

ell t

oler

ated

in p

atie

nts

with

food

alle

rgy.

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151

Optimal diagnosis and management of food allergies

FAH

F-2

Ope

n-la

bel

Patil

et

al, 2

011

6414

/18

patie

nts

com

plet

ed t

he s

tudy

, tak

ing

FAH

F-2

for

6

mon

ths.

The

re w

ere

no s

igni

fican

t di

ffere

nces

in la

bora

tory

pa

ram

eter

s, PF

T r

esul

ts, o

r el

ectr

ocar

diog

ram

find

ings

be

fore

or

afte

r tr

eatm

ent.

The

re w

as a

sig

nific

ant

redu

ctio

n

in b

asop

hil C

D63

exp

ress

ion

at 6

mon

ths.

The

re w

as a

tr

end

tow

ard

redu

ctio

n of

eos

inop

hil a

nd b

asop

hil

num

bers

afte

r tr

eatm

ent.

Thi

s st

udy

dem

onst

rate

s fu

rthe

r sa

fety

and

to

lera

bilit

y of

FA

HF-

2. T

here

may

be

som

e im

mun

olog

ic m

odul

ator

y ef

fect

.

FAH

F-2

Rev

iew

wan

g an

d Li

, 20

1262

Rev

iew

of F

AH

F-2

from

dev

elop

men

t to

Pha

se i

clin

ical

tri

als.

Com

plem

enta

ry

and

alte

rnat

ive

m

edic

ine

Surv

eyN

akan

o et

al,

20

1261

8.4%

of f

ood-

alle

rgic

chi

ldre

n in

Japa

n us

ed c

ompl

emen

tary

an

d al

tern

ativ

e m

edic

ine.

Her

bal t

eas

wer

e m

ost

com

mon

(2

2%),

follo

wed

by

Chi

nese

her

bal m

edic

ine

(18.

5%)

and

la

ctic

aci

d ba

cter

ia (

16%

). 13

.6%

felt

that

com

plem

enta

ry

and

alte

rnat

ive

med

icin

e w

as v

ery

effe

ctiv

e, a

nd 1

1.1%

th

ough

t it

caus

ed s

ome

type

of s

ide

effe

ct.

Am

ong

food

-alle

rgic

Japa

nese

chi

ldre

n, 8

.4%

are

us

ing

com

plem

enta

ry a

nd a

ltern

ativ

e m

edic

ine

to

trea

t th

eir

food

alle

rgy.

OiT

Pean

utR

CT

Ana

gnos

tou

et a

l,

2014

8162

% o

f pat

ient

s re

ceiv

ing

OiT

and

non

e of

the

con

trol

gro

up

achi

eved

des

ensi

tizat

ion.

The

con

trol

pat

ient

s w

ent

on t

o

rece

ive

OiT

in a

sec

ond

phas

e, d

urin

g w

hich

54%

ach

ieve

d

dese

nsiti

zatio

n. G

i sid

e ef

fect

s w

ere

the

mos

t co

mm

on.

Thi

s st

udy

dem

onst

rate

s su

cces

sful

des

ensi

tizat

ion

usin

g pe

anut

flou

r in

a m

ajor

ity o

f par

ticip

ants

; ho

wev

er, i

t do

es n

ot e

valu

ate

long

-ter

m

tole

ranc

e.O

iTPe

anut

RC

Tv

arsh

ney

et a

l,

2011

8216

OiT

pat

ient

s in

gest

ed a

max

imum

dos

e of

5 g

of p

eanu

t

(20

pean

uts)

. Pla

cebo

sub

ject

s to

lera

ted

a m

edia

n do

se o

f 28

0 m

g. O

iT p

atie

nts

had

redu

ced

SPT

whe

al s

ize

and

iL-1

3

and

incr

ease

d pe

anut

-spe

cific

IgG

4.

Dem

onst

rate

s de

sens

itiza

tion

and

imm

unom

odul

atio

n w

ith p

eanu

t O

iT, b

ut d

oes

not

exam

ine

long

-ter

m t

oler

ance

.

OiT

Pean

utR

CT

Sam

pson

et

al,

2011

117

Of n

ine

patie

nts

in th

e om

aliz

umab

trea

tmen

t gro

up,

44%

tole

rate

d .

1 g

pean

ut v

ersu

s 20

% in

the

plac

ebo

grou

p

(n=5

). M

ild a

nd m

oder

ate

adve

rse

even

ts w

ere

repo

rted

in

bot

h gr

oups

(88.

9% p

lace

bo, 7

6.5%

om

aliz

umab

).

The

stu

dy w

as s

topp

ed e

arly

, and

mos

t di

d no

t m

eet

pred

efine

d st

udy

endp

oint

s. S

ome

evid

ence

to

sug

gest

tha

t om

aliz

umab

hel

ps t

o in

crea

se t

he

thre

shol

d to

lera

ted

in p

eanu

t O

iT.

SLiT

Pean

utR

CT

Flei

sche

r et

al,

20

1383

Afte

r 44

wee

ks o

f tre

atm

ent,

70%

of s

ubje

cts

rece

ivin

g SL

iT

tole

rate

d pe

anut

OFC

com

pare

d w

ith 1

5% o

f con

trol

s.SL

iT s

afel

y in

duce

d a

mod

est

leve

l of

dese

nsiti

zatio

n in

the

maj

ority

of 4

0 su

bjec

ts a

ged

12–3

7 ye

ars.

A s

igni

fican

t in

crea

se in

dos

e w

as

tole

rate

d, b

ut n

o co

rrel

atio

n w

as fo

und

betw

een

clin

ical

impr

ovem

ent

and

sige

leve

ls.

SLiT

, OiT

Pean

utR

CT

Chi

n et

al,

2013

84C

ompa

riso

n of

tw

o pr

evio

usly

pub

lishe

d tr

ials

(v

arsh

ney

et a

l82 a

nd S

krip

ak e

t al

99)

rega

rdin

g pe

anut

O

iT v

ersu

s SL

iT.

Ret

rosp

ectiv

e co

mpa

riso

n of

tw

o R

CT

s fo

r O

iT

and

SLiT

in p

eanu

t-al

lerg

ic c

hild

ren.

OiT

pro

vide

d hi

gher

dos

e th

resh

olds

tha

n SL

iT.

OiT

Pean

utPr

ospe

ctiv

e

coho

rtv

icke

ry e

t al

, 20

1488

Of 3

9 en

rolle

d su

bjec

ts, 2

4 co

mpl

eted

a p

roto

col i

nvol

ving

5

year

s of

pea

nut O

iT. A

mon

g th

em, 1

2 (5

0%) h

ad s

usta

ined

un

resp

onsiv

enes

s to

pea

nut 1

mon

th a

fter

disc

ontin

uing

OiT

. C

ompa

red

to th

ose

who

faile

d ch

alle

nge,

thos

e w

ho p

asse

d

had

smal

ler

SPT

whe

al d

iam

eter

s, an

d lo

wer

leve

ls of

sig

e,

Ara

h 1

, and

Ara

h 2

.

Thi

s st

udy

dem

onst

rate

s th

at 5

0% o

f pat

ient

s tr

eate

d w

ith p

eanu

t O

iT fo

r 5

year

s ha

ve

sust

aine

d un

resp

onsi

vene

ss 1

mon

th a

fter

disc

ontin

uing

tre

atm

ent.

whi

le t

hese

res

ults

are

pr

omis

ing,

long

er-t

erm

follo

w-u

p da

ta w

ould

be

help

ful i

n de

term

inin

g ac

quis

ition

of t

oler

ance

.O

iTPe

anut

Pros

pect

ive

co

hort

Jone

s et

al,

2009

8627

/29

patie

nts

unde

rgoi

ng O

iT w

ere

able

to

reac

h ta

rget

do

se o

f pea

nut.

Thr

ough

out

trea

tmen

t, SP

T w

heal

siz

e an

d

sige

dec

reas

ed, w

hile

igG

4 inc

reas

ed.

Dem

onst

rate

d cl

inic

al d

esen

sitiz

atio

n an

d im

mun

e re

gula

tion

with

OiT

to

pean

ut.

(Con

tinue

d)

Journal of Asthma and Allergy 2014:7submit your manuscript | www.dovepress.com

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152

O’Keefe et al

Tab

le 2

(Co

ntin

ued)

Mod

alit

yA

llerg

enT

ype

of

stud

yA

utho

rs,

publ

icat

ion

year

Ref

eren

ceFi

ndin

gsC

omm

ents

OiT

Pean

utPr

ospe

ctiv

e

coho

rtH

ofm

ann

et a

l,

2009

9120

/28

patie

nts

com

plet

ed t

he s

tudy

. On

esca

latio

n da

y,

79%

had

URT

, 68%

Gi s

ympt

oms,

and

18%

mild

whe

ezin

g.

Afte

r bu

ild-u

p ph

ase,

ris

k of

rea

ctio

n w

as 4

6% (

29%

UR

T,

24%

cut

aneo

us).

Ris

k of

rea

ctio

n du

ring

hom

e do

sing

was

3.

5% (

UR

T 1

.2%

, ski

n 1.

1%).

Tre

atm

ent

was

giv

en in

0.7

%

of t

he h

ome

dose

s.

Thi

s st

udy

exam

ined

the

saf

ety

of p

eanu

t O

iT.

Mos

t re

actio

ns o

ccur

red

duri

ng e

scal

atio

n.

Rea

ctio

ns w

ith h

ome

dosi

ng w

ere

rare

.

OiT

Pean

utPr

ospe

ctiv

e

coho

rtBl

umch

en e

t al

, 20

1090

23 c

hild

ren

rece

ived

OiT

with

a r

ush

prot

ocol

, afte

r w

hich

a

med

ian

dose

of 0

.15

g Pe

anut

was

tol

erat

ed. 2

2/23

pat

ient

s

rece

ived

long

-ter

m p

roto

col.

Afte

r 7

mon

ths

of t

reat

men

t,

14 r

each

ed p

rote

ctiv

e do

se (

0.5

g pe

anut

).

Rus

h pr

otoc

ol w

as n

ot e

ffect

ive

and

was

as

soci

ated

with

adv

erse

rea

ctio

ns. L

ong-

term

bu

ild-u

p is

saf

e an

d ef

fect

ive.

OiT

Pean

utPr

ospe

ctiv

e

coho

rtY

u et

al,

2012

9224

pat

ient

s re

ceiv

ed 6

,662

dos

es. 8

4% o

f sym

ptom

s w

ere

m

ild, 1

3% m

oder

ate,

and

3%

sev

ere

(Gi r

eact

ions

req

uiri

ng

epin

ephr

ine)

.

in t

his

stud

y ex

amin

ing

the

safe

ty o

f pea

nut

OiT

, m

ost

reac

tions

wer

e m

ild, t

houg

h so

me

patie

nts

had

seve

re r

eact

ions

req

uiri

ng t

reat

men

t w

ith

epin

ephr

ine.

OiT

Pean

utR

etro

spec

tive

co

hort

was

serm

an e

t al

, 20

1489

352

patie

nts

rece

ived

240

,351

dos

es o

f pea

nut

OiT

. The

re

wer

e 95

rea

ctio

ns r

equi

ring

tre

atm

ent

with

epi

neph

rine

; th

ree

requ

ired

tw

o do

ses.

298

pat

ient

s ac

hiev

ed t

he t

arge

t

mai

nten

ance

dos

e (8

5%).

This

retr

ospe

ctiv

e ch

art r

evie

w e

xam

ines

dat

a fr

om

five

clin

ics

cond

uctin

g pe

anut

OIT

usin

g di

ffere

nt

agen

ts (p

eanu

t, pe

anut

but

ter,

or p

eanu

t flou

r). I

t de

mon

stra

tes

that

a s

igni

fican

t num

ber

of p

atie

nts

have

rea

ctio

ns r

equi

ring

epin

ephr

ine,

and

that

mos

t ar

e ab

le to

rea

ch th

e ta

rget

mai

nten

ance

dos

e.O

iTPe

anut

edito

rial

Man

sfiel

d, 2

013

87Pr

o/co

n ed

itori

al o

f pea

nut

OiT

The

aut

hor

argu

es t

hat

pean

ut O

iT is

rea

dy fo

r cl

inic

al p

ract

ice.

OiT

Pean

utSy

stem

atic

re

view

Shei

kh e

t al

, 201

211

8Sy

stem

atic

rev

iew

of s

ix c

ase

seri

es s

tudi

es w

ith a

tot

al o

f 85

par

ticip

ants

.M

any

part

icip

ants

incr

ease

the

ir t

hres

hold

dos

e w

hile

on

trea

tmen

t. A

dver

se r

eact

ions

wer

e co

mm

on a

nd, t

houg

h us

ually

mild

, som

e w

ere

life-

thre

aten

ing.

Nov

el

imm

unot

hera

pyPe

anut

expe

rim

enta

l te

chni

que

Pasc

al e

t al

, 201

311

9Id

entifi

ed fo

ur r

egio

ns o

f Ara

h 2

that

indu

ced

T-ce

ll

prol

ifera

tion

in p

eanu

t-al

lerg

ic c

hild

ren.

The

se c

ould

pot

entia

lly

be u

sed

for

a pe

ptid

e-ba

sed

vacc

ine

for

food

alle

rgy.

Use

d a

nove

l app

roac

h to

tre

atm

ent

of fo

od

alle

rgy,

but

req

uire

s fu

rthe

r st

udy

befo

re it

is

read

y fo

r cl

inic

al a

pplic

atio

n.O

iTM

ilkR

CT

Pajn

o et

al,

2013

94C

hild

ren

dese

nsiti

zed

with

OiT

wer

e ra

ndom

ized

to

one

of

two

feed

ing

regi

men

s: d

aily

or

twic

e w

eekl

y. T

here

was

no

di

ffere

nce

in a

dver

se r

eact

ions

am

ong

the

two

grou

ps.

Onc

e de

sens

itiza

tion

is a

chie

ved,

a t

wic

e-w

eekl

y m

aint

enan

ce r

egim

en is

as

effe

ctiv

e as

dai

ly

mai

nten

ance

.O

iTM

ilkPr

ospe

ctiv

e

coho

rtN

adea

u et

al,

20

1195

Pilo

t st

udy

in e

leve

n m

ilk-a

llerg

ic c

hild

ren,

usi

ng o

mal

izum

ab

to p

erfo

rm r

apid

ora

l des

ensi

tizat

ion.

9/1

0 ac

hiev

ed t

arge

t

dose

of 1

g d

urin

g ru

sh d

esen

sitiz

atio

n. O

ver

7–11

wee

ks,

9/10

rea

ched

2 g

tar

get.

Rus

h m

ilk d

esen

sitiz

atio

n w

ith o

mal

izum

ab

was

gen

eral

ly s

ucce

ssfu

l and

wel

l tol

erat

ed. A

ll ch

ildre

n ha

d ad

vers

e ev

ents

, but

mos

t w

ere

mild

an

d di

d no

t re

quir

e tr

eatm

ent.

The

re w

as o

ne

even

t re

quir

ing

epin

ephr

ine.

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153

Optimal diagnosis and management of food allergies

OiT

Milk

Pros

pect

ive

co

hort

váz

quez

-Ort

iz

et a

l, 20

1397

81 c

hild

ren

enro

lled.

71.

6% h

ad c

ompl

ete

dese

nsiti

zatio

n an

d

20.9

% p

artia

l des

ensit

izat

ion.

95%

of c

hild

ren

had

reac

tions

, of

whi

ch 9

1% h

ad a

sin

gle

affe

cted

org

an s

yste

m. 2

0 ch

ildre

n (2

5%)

acco

unte

d fo

r 78

% o

f rea

ctio

ns th

at w

ere

freq

uent

, per

siste

nt,

and

unpr

edic

tabl

e. s

ige

.50

, SPT

whe

al d

iam

eter

of .

9 m

m, o

r

Sam

pson

sev

erity

gra

de 2

, 3, o

r 4

at in

itial

DBP

CFC

are

risk

fa

ctor

s fo

r re

actio

n pe

rsist

ence

.

whi

le m

any

child

ren

can

achi

eve

dese

nsiti

zatio

n w

ith m

ilk O

iT, t

here

is a

hig

h ra

te o

f adv

erse

ev

ents

. Dev

elop

men

t of

tol

eran

ce w

as n

ot

disc

usse

d.

OiT

Milk

Pros

pect

ive

co

hort

Gar

cía-

Ara

et

al,

2013

9636

pat

ient

s w

ere

clas

sifie

d ac

cord

ing

to m

ilk-s

IgE

and

trea

ted

w

ith t

wo

dosi

ng p

roto

cols

. 100

% o

f pat

ient

s w

ith s

ige

,

3.5

kUA

/L a

nd 8

8% o

f pat

ient

s w

ith s

ige

.3.

5 kU

A/L

wer

e

dese

nsiti

zed.

75%

of p

atie

nts

had

adve

rse

even

ts d

urin

g

indu

ctio

n, a

nd 6

0% d

urin

g m

aint

enan

ce.

Tol

eran

ce w

as a

chie

ved

earl

ier

with

low

er s

ige.

A

dver

se e

vent

s w

ere

mor

e fr

eque

nt w

ith

high

er s

ige.

OiT

Milk

Pros

pect

ive

co

hort

Kee

t et

al,

2013

985-

year

follo

w u

p of

32

patie

nts

from

tw

o st

udie

s (S

krip

ak

et a

l99 a

nd K

eet

et a

l100 )

. 31%

wer

e

tole

ratin

g fu

ll se

rvin

gs o

f milk

with

min

imal

to

no s

ympt

oms.

Ach

ieve

men

t of

long

-ter

m t

oler

ance

thr

ough

milk

O

iT is

low

.

OiT

–

form

ula

Milk

Pros

pect

ive

co

hort

Bern

i Can

ani e

t al

, 20

1369

260

milk

-alle

rgic

chi

ldre

n ev

alua

ted.

Rate

of a

cqui

sitio

n of

tole

ranc

e w

as h

ighe

r in

gro

ups

that

rec

eive

d ex

tens

ivel

y hy

drol

yzed

cas

ein

form

ula

(43.

6%) o

r eH

CF

+ La

ctob

acillu

s rh

amno

sus

GG

(78.

9%)

com

pare

d to

ric

e, so

y, an

d am

ino

acid

form

ulas

.

eCH

F ac

cele

rate

s ac

quis

ition

of t

oler

ance

in m

ilk-

alle

rgic

chi

ldre

n.

OiT

–

form

ula

Milk

RC

TR

eche

et

al, 2

010

101

92 in

fant

s w

ith ig

e-m

edia

ted

milk

alle

rgy

wer

e ra

ndom

ized

to

rec

eive

hyd

roly

zed

rice

form

ula

or e

HC

F. O

ne in

fant

in

the

eHC

F gr

oup

had

an im

med

iate

rea

ctio

n. N

o st

atis

tical

ly

sign

ifica

nt d

iffer

ence

in a

cqui

sitio

n of

milk

tol

eran

ce b

etw

een

th

e tw

o gr

oups

.

Hyd

roly

zed

rice

form

ula

is a

saf

e al

tern

ativ

e fo

r ch

ildre

n w

ith m

ilk a

llerg

y.

OiT

Milk

Rev

iew

Yeu

ng e

t al

, 201

293

Coc

hran

e Re

view

exa

min

ing

five

stud

ies

with

a to

tal o

f 19

6 pa

rtic

ipan

ts (1

06 tr

eatm

ent,

90 c

ontr

ol).

Prim

ary

outc

ome

of

stu

dies

was

des

ensit

izat

ion;

tole

ranc

e w

as n

ot a

sses

sed.

62%

of

the

OiT

gro

up w

ere

able

to to

lera

te a

full

serv

ing

of m

ilk

vers

us 8

% o

f con

trol

s. 25

% o

f the

OiT

gro

up c

ould

inge

st a

pa

rtia

l ser

ving

of m

ilk v

ersu

s no

ne in

the

cont

rol g

roup

.

Side

effe

cts

in m

ilk O

iT a

re c

omm

on, b

ut t

he

maj

ority

are

mild

. Lon

g-te

rm t

oler

ance

has

not

ye

t be

en a

sses

sed.

Mai

ntai

ning

des

ensi

tizat

ion

requ

ires

reg

ular

con

sum

ptio

n of

the

hig

hest

to

lera

ted

dose

of m

ilk.

OiT

egg

RC

TBu

rks

et a

l, 20

1210

3A

fter

10 m

onth

s of

egg

OiT

, 55%

of t

he t

reat

men

t gr

oup

and

no

ne o

f the

pla

cebo

gro

up p

asse

d O

FC. A

fter

22 m

onth

s,

75%

of t

he O

iT g

roup

wer

e de

sens

itize

d. A

fter

2 m

onth

s

of a

void

ing

egg

cons

umpt

ion,

onl

y 28

% p

asse

d O

FC.

egg

OiT

can

suc

cess

fully

des

ensi

tize

mos

t ch

ildre

n, b

ut s

usta

ined

unr

espo

nsiv

enes

s is

ac

hiev

ed o

nly

in a

sm

all s

ubse

t.

OiT

egg

RC

TM

eglio

et

al, 2

013

104

Of a

gro

up o

f ten

egg

-alle

rgic

chi

ldre

n tr

eate

d w

ith r

aw e

gg

OiT

, 80%

ach

ieve

d th

e ta

rget

dos

e ov

er a

6-m

onth

per

iod.

O

ne fa

iled

and

anot

her

achi

eved

par

tial d

esen

sitiz

atio

n.

20%

of t

he c

ontr

ol g

roup

ach

ieve

d to

lera

nce

afte

r 6

mon

ths.

Thi

s st

udy

dem

onst

rate

s ef

fect

ive

dese

nsiti

zatio

n bu

t do

es n

ot e

xam

ine

long

-ter

m t

oler

ance

. whi

le

this

stu

dy is

enc

oura

ging

, it

had

smal

l num

bers

and

a

shor

t du

ratio

n.O

iTeg

gPr

ospe

ctiv

e

coho

rtito

h et

al,

2010

106

Rus

h O

iT in

six

egg

-alle

rgic

chi

ldre

n, w

here

by a

fter

12 d

ays

al

l par

ticip

ants

rea

ched

the

tar

get

dose

of o

ne w

hole

egg

, af

ter

whi

ch t

hey

rem

aine

d on

mai

nten

ance

tw

ice

a w

eek.

A

t 12

mon

ths,

the

re w

as d

ecre

ased

egg

-sig

e an

d in

crea

sed

ig

G4.

The

re w

ere

no s

erio

us r

eact

ions

and

no

part

icip

ants

re

quir

ed e

pine

phri

ne.

Rus

h O

iT t

o eg

g w

as w

ell t

oler

ated

in t

he g

roup

of

six

chi

ldre

n.

(Con

tinue

d)

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154

O’Keefe et al

Tab

le 2

(Co

ntin

ued)

Mod

alit

yA

llerg

enT

ype

of

stud

yA

utho

rs,

publ

icat

ion

year

Ref

eren

ceFi

ndin

gsC

omm

ents

OiT

egg

Pros

pect

ive

co

hort

Gar

cía

Rod

rígu

ez

et a

l, 20

1110

7in

rus

h O

iT in

23

egg-

alle

rgic

chi

ldre

n ov

er 5

–10

days

, 78

.3%

had

rea

ctio

ns, b

ut n

one

wer

e se

riou

s. 2

0/23

wer

e

succ

essf

ully

des

ensi

tized

. At

6 m

onth

s, t

here

wer

e

decr

ease

s in

sig

e an

d SP

T s

ize

and

incr

ease

s in

igG

4 and

C

D4+

Fox

P3+

cells

.

Des

crib

es a

pro

toco

l for

egg

des

ensi

tizat

ion

that

is

tol

erat

ed b

y m

ost

egg-

alle

rgic

pat

ient

s as

wel

l as

imm

unol

ogic

cha

nges

pos

sibl

y as

soci

ated

with

de

sens

itiza

tion.

OiT

egg

Pros

pect

ive

co

hort

Leon

ard

et a

l,

2012

102

89%

of p

atie

nts

chal

leng

ed t

o ba

ked

egg

wer

e to

lera

nt. 5

3%

of t

hose

bec

ame

regu

lar

egg

tole

rant

as

wel

l. A

mon

g th

ose

w

ho r

eact

ed t

o ba

ked

egg,

61%

sub

sequ

ently

tol

erat

ed it

an

d 26

% t

oler

ated

reg

ular

egg

. Tho

se w

ho t

oler

ated

bak

ed

egg

had

low

er e

gg-s

ige.

in s

ubje

cts

inge

stin

g ba

ked

egg,

egg

SPT

w

heal

siz

e an

d ov

albu

min

- an

d ov

omuc

oid-

sige

all

decr

ease

d,

whi

le o

valb

umin

and

ovo

muc

oid-

spec

ific

IgG

4 inc

reas

ed.

Bake

d eg

g ch

alle

nges

sho

uld

be p

erfo

rmed

am

ong

egg-

alle

rgic

chi

ldre

n, a

s m

ost

egg-

alle

rgic

chi

ldre

n to

lera

te b

aked

egg

and

incl

usio

n of

bak

ed e

gg in

th

e di

et m

ay h

aste

n th

e re

solu

tion

of e

gg a

llerg

y.

OiT

egg

Pros

pect

ive

coho

rtO

jeda

et

al, 2

012

108

80.6

% o

f the

sub

ject

s in

the

inte

ntio

n-to

-tre

at g

roup

ac

hiev

ed d

esen

sitiz

atio

n to

egg

. Fou

r ca

ses

requ

ired

tr

eatm

ent

with

epi

neph

rine

at

hom

e. B

aked

egg

-tol

eran

t

patie

nts

wer

e m

ore

likel

y to

ach

ieve

raw

egg

tol

eran

ce.

Thi

s st

udy

dem

onst

rate

s ef

fect

ive

dese

nsiti

zatio

n bu

t do

es n

ot e

xam

ine

long

-ter

m t

oler

ance

. The

au

thor

s’ d

efini

tion

of a

naph

ylax

is a

s in

volv

ing

thre

e or

mor

e or

gan

syst

ems

may

exp

lain

why

th

ere

wer

e fe

w c

ases

of a

naph

ylax

is.

OiT

egg

Pros

pect

ive

coho

rtT

orta

jada

-Gir

bés

et

al,

2012

105

19 e

gg-a

llerg

ic c

hild

ren

wer

e gi

ven

incr

easi

ng a

mou

nts

of e

gg

at w

eekl

y in

terv

als.

89.

5% o

f sub

ject

s ac

hiev

ed t

oler

ance

to

th

e ta

rget

dos

e. T

here

was

no

anap

hyla

xis

duri

ng t

he O

iT

phas

e, t

houg

h tw

o pa

rtic

ipan

ts w

ithdr

ew fr

om t

he s

tudy

as

th

ey h

ad a

naph

ylax

is w

ith t

he in

itial

dos

e.

Thi

s st

udy

dem

onst

rate

s ef

fect

ive

dese

nsiti

zatio

n to

egg

but

doe

s no

t ex

amin

e lo

ng-t

erm

tol

eran

ce.

SLiT

Peac

hR

CT

Gar

cía

et a

l, 20

1011

0In

des

crib

ing

sens

itiza

tion

profi

les

of p

each

-alle

rgic

in

divi

dual

s, r

Pru

p 3

was

the

mos

t re

cogn

ized

(83

.3%

),

follo

wed

by

nArt

v 3

(25

.9%

), rM

al d

4 (

24.1

%),

and

rMal

d

1 (1

8.5%

). si

ge t

o rP

ru p

3 r

ose

in b

oth

grou

ps b

ut

rem

aine

d el

evat

ed o

nly

in t

he t

reat

men

t gr

oup.

Pea

ch

SPT

whe

al s

ize

decr

ease

d in

the

tre

atm

ent

grou

p.

rPru

p 3

was

the

mos

t co

mm

on a

ntig

en

reco

gniz

ed b

y pe

ach-

alle

rgic

indi

vidu

als.

Thi

s st

udy

dem

onst

rate

s a

decr

ease

in S

PT w

heal

siz

e in

the

tr

eatm

ent

grou

p, b

ut t

hey

did

not

perf

orm

OFC

.

SLiT

Peac

hR

CT

Fern

ánde

z-R

ivas

et

al,

2009

109

Afte

r 6

mon

ths

of S

LiT

with

Pru

p 3

ext

ract

, the

tre

atm

ent

gr

oup

tole

rate

d hi

gher

dos

es o

f pea

ch, h

ad s

mal

ler

SPT

, and

in

crea

sed

igG

4. N

o sy

stem

ic r

eact

ions

wer

e ob

serv

ed, b

ut

loca

l rea

ctio

ns w

ere

com

mon

.

Dem

onst

rate

s ef

fect

ive

dese

nsiti

zatio

n an

d sa

fety

of

SLi

T t

o pe

ach

usin

g Pr

u p

3 ex

trac

t.

effe

ct o

f coo

king

m

etho

d on

pe

anut

alle

rgen

s

Pean

utex

peri

men

tal

tech

niqu

eK

im e

t al

, 201

312

0ex

amin

ed e

ffect

of c

ooki

ng m

etho

d on

pea

nut

prot

eins

. A

ra h

2 a

nd 3

wer

e th

e m

ost

impo

rtan

t ep

itope

s. A

ra h

2

was

enh

ance

d by

boi

ling,

roa

stin

g, a

nd fr

ying

pea

nuts

and

de

crea

sed

by p

ickl

ing

(vin

egar

). A

lso,

the

re w

as le

ss ig

e

bind

ing

in v

ineg

ar. A

ra h

3 w

as e

nhan

ced

by a

ll tr

eatm

ents

.

Coo

king

met

hods

will

alte

r ep

itope

s in

pea

nut,

alth

ough

the

clin

ical

sig

nific

ance

of t

his

is n

ot

esta

blis

hed.

Milk

Rev

iew

Res

tani

et

al, 2

009

121

Cho

ices

in c

ow’s

milk

(fil

trat

ion

not

effe

ctiv

e); a

ltern

ativ

es

to c

ow’s

milk

(do

nkey

, mar

e, c

amel

, etc

); co

mor

bid

beef

al

lerg

y.

Milk

alle

rgy

is a

n in

crea

sing

pro

blem

in in

fanc

y.

Furt

her

rese

arch

sho

uld

be t

arge

ted

to e

valu

atin

g m

anag

emen

t of

milk

alle

rgy.

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155

Optimal diagnosis and management of food allergies

Rev

iew

Sanz

et

al, 2

011

5U

se o

f mic

roar

ray

com

pone

nt-b

ased

dia

gnos

is in

food

alle

rgy.

Mic

roar

ray

tech

nolo

gy t

o ev

alua

te s

ige

to fo

ods

is

a he

lpfu

l adv

ance

in fo

od a

llerg

y di

agno

sis.

Abb

revi

atio

ns: D

BPC

FC, d

oubl

e-bl

ind,

pla

cebo

-con

trol

led

food

cha

lleng

e; e

Ai,

epin

ephr

ine

auto

inje

ctor

; eH

CF,

ext

ensi

vely

hyd

roly

zed

cow

’s m

ilk fo

rmul

a; F

AH

F-2,

food

alle

rgy

herb

al fo

rmul

a 2;

FA

QO

L, fo

od a

llerg

y he

alth

–rel

ated

qu

ality

of l

ife; G

i, ga

stro

inte

stin

al; i

ge, i

mm

unog

lobu

lin e

; igG

4, im

mun

oglo

bulin

G, t

ype

4; O

FC, o

pen

food

cha

lleng

e; O

iT, o

ral i

mm

unot

hera

py; O

R, o

dds

ratio

; PFT

, pul

mon

ary

func

tion

test

; QO

L, q

ualit

y of

life

; RC

T, r

ando

miz

ed

cont

rolle

d tr

ial;

sIgE

, spe

cific

IgE;

SLI

T, s

ublin

gual

imm

unot

hera

py; S

PT, s

kin

pric

k te

st; U

RT

, upp

er r

espi

rato

ry t

ract

; VIT

AL,

Vol

unta

ry In

cide

ntal

Tra

ce A

llerg

en L

abel

ling.

sige and component testingMeasurement of IgE levels to a specific antigen is another

commonly employed method in the diagnosis of food allergies.

Like SPT, it assesses sensitization rather than clinical food

allergy.17 Component testing strives to delineate sensitized

patients from those who will react to a given food. Peanut is

one of the more extensively investigated foods in this regard.

In evaluating peanut-sIgE, van Nieuwaal et al18 found higher

cutoffs for predicting OFC failure compared to previous

studies. Ninety percent of participants failed the peanut chal-

lenge at an sIgE of 24.8 kUA/L, and 95% at 43.8 kUA/L. The

authors attributed these findings to their study population,

many of whom were diagnosed with peanut allergy without

undergoing DBPCFC. In distinguishing peanut sensitization

from reactivity, elevated levels of Ara h 2 tend to be associ-

ated with a reactive phenotype,19,20 whereas 89.5% of children

with elevated Ara h 8 can safely ingest peanut.21 In comparing

peanut-sIgE, Ara h 2, and OFC results, sIgE was the most

sensitive test 0.93 (93%), while Ara h 2 was the most specific

and had the best positive predictive value.19 Researchers have

shown similar results in peanut-allergic Asian children.22 In

an effort to develop a more accurate test, Lin et al examined

specific sequences of the peanut components and found

that using a combination of four peptides Ara h 1, 2, and 3

had 90% sensitivity and 95% specificity.23 The biomarkers

generally used to monitor the effect of immunotherapy are

sIgE and SPT wheal size. Kulis et al24 examined the effect

of peanut sublingual immunotherapy (SLIT) on salivary

immunoglobulin A levels and found a transient elevation in

the treatment group, but, by 1 year, there was no significant

difference between the two groups.

Most children with egg allergy will outgrow it.

Montesinos et al examined the relationships between sIgE

directed towards egg white, ovalbumin, and ovomucoid, and

demonstrated that these biomarkers were lower in subjects

who outgrew their egg allergy.25 Another recent finding

in egg allergy is that many egg-allergic children are able

to tolerate baked egg. sIgE to egg white, ovalbumin, and

ovomucoid tends to be lower in children who are tolerant to

baked egg.26,27

Further studies have examined the role of diagnostic

testing in sesame, wheat, and soy allergy. For sesame,

sIgE .7 kUA/L or an SPT wheal size .6 mm were

both .90% specific in predicting the results of an OFC.28 In

a Japanese cohort, the median sIgE level in allergic children

was 4.31 kUA/L for wheat and 3.89 kUA/L for soybean.29

It has been previously hypothesized that immunoglobu-

lin G (IgG)-mediated reactions may be involved with food

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O’Keefe et al

• 11,922 titles excluded because they did not discuss diagnosis or management

217

100

12,139

• 117 titles excluded after reading abstracts

• 100 titles included in final review

Figure 1 Results of the database search for literature about food allergy diagnosis and management.

hypersensitivity, and, as such, some health care practitioners

measure food-specific IgG levels. However, in a cohort of

5,394 Chinese adults, there was no relationship between

food-specific IgG levels and allergic symptoms.30 Given that

increased IgG levels to food allergens may indicate tolerance

rather than allergy, this test is not used by allergists in their

evaluation.31

Food challengesFood challenges involve feeding the patient incremental

doses of a suspected food and observing them for clinical

reaction. Ideally, this is done in a double-blind, placebo-

controlled manner. However, it is more practical to administer

an OFC that is neither blinded nor placebo controlled. Food

challenges may be performed to confirm the diagnosis of

allergy or to monitor for resolution, and are often necessary

due to the poor sensitivity and specificity of SPT and sIgE

testing. Fleischer et al found that most children diagnosed

with food allergy on the basis of immunoassays were able

to reintroduce the suspected food into their diet following

challenge.32 Food challenges are also useful in establishing

the diagnosis of non-IgE-mediated processes that cannot be

detected by SPT or sIgE testing.33 When performed in an

appropriate setting, OFCs are an extremely safe procedure. In

an evaluation of 701 OFCs performed in 521 patients, 18.8%

elicited a reaction. Only 1.7% of those who reacted required

treatment with epinephrine.34 Calvani et al reported similar

results: among 544 OFCs, 48.3% of patients reacted, although

65.7% had mild reactions; only 2.7% required treatment with

epinephrine.35 OFCs have been demonstrated to be a highly

reproducible and valid strategy for establishing the diagnosis

of food allergy. A recent study exemplified this, with 100%

correlation between a positive DBPCFC and a positive single-

blind OFC among patients with peanut allergy.36

OFCs have been established as a safe and effective way

to diagnose milk allergy.37 An OFC for milk is important for

several reasons. Many children will become milk tolerant

with time. In fact, between 58.7% and 66% of children with

suspected milk allergy will be tolerant to an OFC.37,38 Similar

to those with an egg allergy, most milk-allergic children can

tolerate baked milk. Bartnikas et al reported that 83% of the

milk-allergic children they challenged were able to tolerate

baked milk in their diet. In particular, they found that no

child with an SPT wheal diameter ,7 mm failed the baked

milk challenge, and that 90% of those with a wheal diameter

under 12 mm passed the baked milk challenge.39 Elimination

diets are detrimental to health as they can be associated with

nutritional deficiencies and increased anxiety among patients

and families. Liberalizing the diet to include safe foods that

are tolerated by the patient is essential in improving quality

of life.40 OFCs are associated with a transient increase in

parental anxiety, but, in the long-term, parents and patients

report improved quality of life.41,42

There are several methods by which OFC may be con-

ducted, with many clinicians using individualized protocols.

These protocols can vary in terms of timing, dosing, the agent

used, and the definition of a positive or negative challenge. In

an egg OFC, Escudero et al challenged patients to both dried

egg white and raw egg white. They found that 25% of the

patients reacted to both, and 75% of the patients reacted to

neither, indicating that dried egg white can be used to evalu-

ate raw egg.43 Dried egg white offers several advantages over

raw egg white, including storage capacity and palatability.

Similarly, Winberg et al sought to validate recipes for use in

DBPCFCs to egg, milk, cod, soy, and wheat. Using the same

liquid test vehicle for each allergen, they found that children

were unable to differentiate test from control doses.44 This

provides clinicians with validated recipes that are easy to

prepare and effective in concealing antigen.

OFCs and blind food challenges to evaluate immediate

IgE-mediated food allergy are typically started with 0.1%

to 1% of the total challenge food. If known, the initial OFC

dose should be lower than the expected threshold dose.

According to one approach, the total amount that should be

administered during a gradually escalating OFC equals 8–10

g of a dry food, 16–20 g of meat or fish, and 100 mL of wet

food (eg, apple sauce). The recommended dosing interval

is 15 minutes.45

ManagementPrimary preventionThere are many theories regarding the origins of allergy.

While we do not fully understand the etiology of allergic dis-

ease, much research has focused on how it may be prevented.

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Optimal diagnosis and management of food allergies

In a cohort of infants with likely milk or egg allergy, Sicherer

et al found that maternal peanut consumption during preg-

nancy, as well as sIgE to milk and peanut, were linked to an

increased risk of having peanut-sIgE .5 kUA/L.46 Similar

findings have been reported for tree nut and sesame seeds.47

It is important to note that these studies evaluated sensitiza-

tion rather than reactivity. Mothers of peanut-allergic children

reported higher consumption of peanuts during pregnancy and

breastfeeding compared to mothers of non-allergic subjects.48

However, the retrospective design of the study makes recall

bias a likely explanation for this finding. In two recent cohort

studies assessing clinical peanut allergy, it was reported

that higher maternal peanut intake during pregnancy was

associated with a reduced risk of peanut-allergic reaction in

offspring.49,50

Other studies have assessed the influence of maternal

antioxidants consumption and polyunsaturated fatty acid

supplementation during pregnancy on allergic disease in

children. West et al reported that increased dietary levels of

copper during pregnancy were associated with lower rates

of wheeze and eczema, but had no effect on food allergy

in offspring.51 There was no association between polyun-

saturated fatty acid supplementation during pregnancy and

prevention of allergic disease in offspring.52

Beyond pregnancy, several studies have assessed interven-

tions in infancy that may prevent the development of food

allergy. Three studies have assessed the role of probiotic

supplementation during infancy on allergic disease in child-

hood but failed to establish an association.53–55 Similarly, no

association was found between fish oil supplementation in

infancy and allergic disease.56 Other studies have examined

how the timing of food introduction influences acquisition

of tolerance. In a case-control study, Grimshaw et al reported

that infants with food allergy at 2 years of age tended to have

been introduced to solids at less than 16 weeks and were

less likely to have received breast milk when cow’s milk

was introduced.57 Other studies have examined the timing

of introduction of specific foods, namely milk and egg. In

a prospective cohort, Katz et al found an overall incidence

of IgE-mediated milk allergy of 0.5%. The median age of

introduction among milk-tolerant infants was 61.6 days,

compared to 116.1 days for milk-allergic infants.58 Koplin

et al reported that, compared to introduction of egg between

4 and 6 months of age, delayed introduction was associated

with a higher risk of egg allergy, with an odds ratio (OR)

of 1.6 for those introduced to egg at 10–12 months and 3.4

for those introduced when older than 12 months.59 While

the optimal timing for the introduction of foods to induce

tolerance remains under investigation, the above studies

suggest that delaying food introduction beyond 4–6 months

of age may increase the risk for food allergy rather than

prevent its development.

Fewer studies have examined factors in childhood that

are associated with the development of allergic disease.

In a cross-sectional study examining children in an allergy

clinic, DeMuth et al found that history of taking antacid

medication in children according to parental report was

associated with an increased prevalence of food aller-

gy.60 This may be explained by the effects of antacids on

gastric pH and subsequent influence on the digestion of

proteins.

Complementary and alternative medicinesAn estimated 8.4% of Japanese children use complementary

and alternative medicines in the management of their food

allergies. Among these, herbal teas are the most common

(22%), followed by Chinese herbal medicine (18.5%) and

lactic acid bacteria (16%).61 Of these therapies, most research

has focused on a type of Chinese herbal medicine, food

allergy herbal formula 2 (FAHF-2). FAHF-2 is a nine-herb

formula manufactured in China using a standardized process

and monitored for contaminants using high-performance

liquid chromatography.62 Two studies have demonstrated

the safety and tolerability of FAHF-2 and offered some evi-

dence of an immunologic modulatory effect. Neither of these

studies examined the clinical effect of this formulation.63,64

Allergen avoidanceSeveral steps are required for the allergic patient to success-

fully avoid a particular allergen. They must be appropriately

diagnosed, clearly understand what foods to avoid, and

be able to identify the allergen on a label. For children, there

is an added layer of complexity as their caregivers must be

proficient in these skills as well.

There is anxiety associated with the diagnosis of food

allergy. A study of seafood-allergic children found that 25%

of their parents could not recall dietary advice provided by

a physician. Nonetheless, 89% of them implemented a safe

diet, although it was often more restrictive than needed.

Approximately one in five patients had recurrent reactions

following diagnosis. Prescription of an EAI was associated

with improved adherence to the diet.65 In studies of milk-

allergic children, 85% adhered to a milk-free diet, although

this cohort received special infant formula reimbursement,

which may bias the sample. Moreover, it is unclear whether

these children were avoiding milk because of IgE-mediated

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O’Keefe et al

reactions.66 Milk is prevalent in many foods and may be a

“hidden” allergen. Accordingly, accidental exposures to milk

are common and observed in up to 40% of children with milk

allergy, although these reactions are usually mild (53%).67

There are several options available for milk-allergic patients.

One study examined camel milk as an alternative and found

it was well tolerated.68 Berni Canani et al examined a new

amino acid formula and found that this was a safe alternative

for children with milk allergy.69

Labeling practices to alert consumers to food allergens

are varied among manufacturers, with many products bearing

a “may contain” precautionary label. In an Australian study,

65% of products had precautionary labels for an allergen that

was not listed in the ingredients.70 There is a high degree of

consumer confusion when it comes to food labeling, with

less than 5% of the general population able to correctly

identify more than 50% of the terms associated with a given

allergen.71 Among food labels, “not suitable” was found to be

the most effective in deterring purchase of a product among

food-allergic individuals and members of their households.72

Current food-labeling practices benefit neither the consumer

nor the manufacturer. The use of a standardized process

would be beneficial to both these groups.73

Young children with food allergies require assistance

from adults to efficiently avoid allergens. Food is consumed at

school, and the teacher plays an important role in the safety of

food-allergic children. A survey of Mississippi, USA schools

found that 97% had at least one food-allergic child, but only

30% had action plans for these students. Schools were more

likely to have action plans when the school nurse had received

appropriate information from a physician.74 Similar findings

were reported in a Korean study, where 71% of schools relied

on parental report of food allergy and 47% had experienced

student visits to a school health room due to food allergy. More

than 80% relied on self-care without school-wide measures for

food allergies.75 Further, there are many misconceptions among

teachers regarding food allergy and anaphylaxis. In a survey

of primary school teachers, pollen was thought to be the most

common agent to cause anaphylaxis. Among foods, egg and

strawberry were the leading suspects. Only 10% of teachers

surveyed were aware of EAI and only 4% knew how to admin-

ister it.76 Training programs on the recognition and management

of anaphylaxis should be implemented for teachers and other

caregivers. Anaphylaxis action plans can be written by physi-

cians and provided for distribution in daycares and schools.

eAisMost individuals with IgE-mediated food allergy are advised

to carry an EAI in case of accidental exposure. There are

many barriers to the successful use of an EAI, including

the ability to recognize the symptoms of anaphylaxis, the

availability of an EAI, and understanding of how to use the

EAI. There are additional psychological factors at play, as

many patients and parents with an EAI do not use it during

anaphylaxis, mostly for reasons relating to fear.8 In almost

50% of cases, an EAI is not carried by individuals with food

allergy.77–79 Barriers to EAI availability include having the

device on one’s person and having a device that has not

expired. Similarly, many patients are not skilled in the use

of their EAIs, with 62%–87% demonstrating errors in use.

Repeated instruction can improve both self-carry practices

and the individual’s ability to use an EAI.77,79 While pre-

scription of an EAI is often necessary, it does impact quality

of life. Pinczower et al found that prescription of an EAI

negatively impacted health-related quality of life, along with

being allergic to multiple foods, a history of severe reaction,

and patient age 7–12 years.80

immunotherapyImmunotherapy is an attractive option for the treatment

of food allergies, as its goal is to induce tolerance in the

subject. Patients are considered to be tolerant when they

can safely consume the food without following a daily oral

food regimen to maintain clinical non-reactivity. In most oral

immunotherapy (OIT) protocols, small amounts of allergen

are administered orally to patients in gradually increasing

amounts, with the immediate goal to induce desensitization.

With desensitization, the treated patient manifests a decreased

response to the ingested food allergens but must continue to

take daily food doses.

Peanut is one of the most common food allergens, and

is of great concern given that accidental ingestion of even a

very small amount can cause life-threatening reactions and

that peanut allergy is typically life-long.

Allergen-specific OIT for peanut allergy aims to induce

desensitization and, potentially, tolerance to peanut. However,

at present, there is still considerable uncertainty about the

effectiveness and safety of this approach.

Three randomized controlled studies have been published

on this subject. Anagnostou et al conducted a randomized

controlled trial (RCT) of peanut OIT using peanut flour

in two phases. In the first phase, 62% of 39 participants

achieved desensitization after 6 months of OIT, defined

as a negative peanut challenge to 1,400 mg of peanut

protein. In the control group, who avoided peanuts, there

were no participants who achieved desensitization. In the

second phase, the control group underwent OIT, with 54%

achieving desensitization. Side effects were generally mild,

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Optimal diagnosis and management of food allergies

with gastrointestinal complaints being the most common.81

Varshney et al randomized 28 subjects to receive either OIT

with peanut flour or placebo. Initial escalation, build-up, and

maintenance phases were followed by an OFC at 1 year with

titrated skin prick tests and laboratory studies performed at

regular intervals. Three subjects in the treatment group with-

drew early because of side effects, but all remaining peanut

subjects (n=16) ingested the maximum cumulative dose of

5,000 mg (approximately 20 peanuts) after 1 year versus 280

mg in the placebo group (P,0.001). Several immunological

changes accompanied successful completion of the OIT pro-

tocol: decreased SPT wheal size and Th2 cytokine production

and increased IgG4 and Treg cells. There was no significant

change in peanut-sIgE levels. Adverse effects were frequent,

but the majority were mild.82

Fleischer et al also published an RCT in 2013 to inves-

tigate safety, efficacy, and immunologic effects of peanut

SLIT in 40 peanut-allergic children. After 44 weeks of SLIT,

14 of 20 (70%) subjects receiving peanut SLIT were respond-

ers, compared with three of 20 (15%) subjects receiving

placebo (P,0.001). In peanut SLIT responders, the median

successful consumed dose increased from 3.5 to 496 mg.

After 68 weeks of SLIT, the median successful consumed

dose significantly increased to 996 mg. With regard to side

effects, of 10,855 peanut doses administered through to

week 44, 63.1% of patients were symptom free; excluding

oropharyngeal symptoms, 95.2% were symptom free.83

In 2013, Chin et al published a letter to an editor to

retrospectively compare two RCTs of OIT versus SLIT

in peanut-allergic children. They found that, after 2 years,

OIT was associated with greater immunological changes in

sIgE and IgG4 levels basophil activation, and IgE/IgG

4 ratio.

Clinically, they found that dose thresholds were lower and

more variable during DBPCFC at 12 months in SLIT versus

OIT.84 Additionally, other small, uncontrolled trials show

suggestive evidence that OIT can increase the threshold dose

for peanut exposure.85–87

There are few studies published on long-term outcomes

of peanut OIT. Vickery et al prospectively followed a group

of patients who underwent 5 years of treatment with peanut

OIT. They found that 12 of 24 patients (50%) had sustained

unresponsiveness to peanut 1 month after discontinuing

therapy.88 Adverse effects are common, but OIT appears to

be relatively safe if administered in a carefully monitored set-

ting. Nevertheless, there remains concern about safety, with

several studies having evaluated this. In a retrospective chart

review examining data from five clinics performing peanut

OIT, Wasserman et al reported that, among 352 patients

receiving 240,351 doses of OIT, there were 95 reactions

requiring treatment with epinephrine.89 Two studies have

evaluated home dosing, and reported reactions in 2.6%–3.7%

of total daily home doses.90,91 In one of these studies, two

reactions required epinephrine.91 In the RCT published by

Varshney et al,82 47% of the patients had mild-to-moderate

side effects requiring antihistamines during the initial rush

phase, with two patients requiring epinephrine. During the

build-up phase and home doses, none of the peanut OIT

patients required epinephrine.

Hofmann et al found that patients were more likely to

develop significant allergic symptoms during the initial

escalation day than during other phases. Upper respiratory

tract (79%) and abdominal (68%) symptoms were the most

frequent symptoms at that phase. The risk of having any

symptom after the build-up phase was 46% and the risk of

reaction with home dosing was 3.5%.91

Yu et al presented data of an ongoing Phase I single-center

trial of peanut OIT. Symptoms were mostly mild (84%) and

self-resolved or were resolved with antihistamines; 13% were

moderate and 3% were severe. Of the severe symptoms, three

gastrointestinal reactions required epinephrine. Abdominal

pain was the most common reaction, followed by oropharyn-

geal and lip pruritus. Respiratory symptoms were rare.92

OIT has been explored for other common food allergens

including milk and egg. In 2012, Yeung et al published a

Cochrane Review on milk OIT (MOIT). At that time, the

authors identified five RCTs in order to compare OIT to

placebo or avoidance. A total of 196 (106 treatment and

90 control) children were enrolled in these studies. The

primary outcome of these studies was successful desensitiza-

tion, but long-term tolerance was not assessed. According to

this Cochrane Review, MOIT was proved to be an effective

method of inducing (partially) desensitization. Yeung et al

reported that 62% of the children in the MOIT group could

tolerate 200 mL of milk versus 8% in the control group.

Twenty-five percent of the children tolerated 10–184 mL of

milk versus 0% in the control group. In general, the authors

described low-quality studies with small numbers and dif-

ferent treatment protocols.93

Since that publication, there has been only one RCT per-

formed, which was by Pajno et al in 2013 and which compared

two different maintenance regimens (daily milk versus milk

twice a week) over 1 year following successful cow’s milk

desensitization. No difference was found in clinical efficacy

or adverse effects between the two groups. The levels of

sIgG4, sIgE and SPT wheal size were comparable between

the intervention and control groups.94

In 2011, Nadeau et al published a pilot study in

which they performed rush desensitization to milk using

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O’Keefe et al

omalizumab. This protocol was successful in 9/10 of the

patients. Although all of the patients experienced adverse

reactions, most of these were mild and only one case required

epinephrine.95

A major pitfall for OIT in general is the frequency of

adverse events. Although most are mild and self-limited,

there is a risk of severe reactions necessitating treatment with

epinephrine. Two studies examined predictors of achieving

tolerance and adverse effects. García-Ara et al evaluated the

efficacy and safety of an OIT protocol according to the level

of sIgE. They found that the lower the sIgE level at baseline,

the earlier tolerance was achieved, and that adverse effects

were more frequent when sIgE levels were higher.96 Vázquez-

Ortiz et al identified three variables associated with reaction

persistence throughout the OIT: cow milk-sIgE levels of at

least 50 kUA/L, SPT wheal size of 9 mm and Sampson

severity grades 2, 3 and 4 at baseline food challenge.97

Currently, there is no evidence that MOIT can induce

long-term tolerance. In a letter to the editor, Keet et al98

published a follow-up of two studies of MOIT (cow’s milk)

after 5 years to evaluate cow’s milk consumption, symp-

toms, and potential predictors of long-term outcomes. The

first study, undertaken by Skripak et al, was a double-blind,

placebo-controlled trial with 20 children.99 The second, per-

formed by Keet et al, was an open-label randomized trial of

OIT versus SLIT with 30 children.100 Sixteen subjects were

eligible from each study and they were followed up after a

median of 4.5 years.

Thirty one percent of patients could tolerate full serv-

ings of cow’s milk with minimal or no symptoms. There are

several limitations of this report as there was no follow-up

serology or SPT, no control group, and no data for quality

of life before and after treatment.98

Two studies have evaluated dietary management strat-

egies other than OIT in milk-allergic children. The first

study, published in 2010 by Reche et al, compared the clini-

cal tolerance of a hydrolyzed rice protein formula with an

extensively hydrolyzed cow’s milk formula (EHCF) in infants

with IgE-mediated cow’s milk allergy. The authors found

no significant differences regarding tolerance achievement,

adverse reactions, sIgE level, growth, or clinical tolerance.101

In a 2013 trial comparing five feeding regimens in milk-

allergic children (EHCF, EHCF + Lactobacillus rhamnosus

GG, hydrolyzed rice formula, soy formula, and amino acid

formula), milk-allergic children who received EHCF alone

or in combination with L. rhamnosus GG achieved tolerance

at 12 months. Significantly more children achieved tolerance

after 12 months than their peers who received hydrolyzed

rice formula, soy formula, or amino acid-based formula.69

Both studies were relatively small and larger sample sizes

may be needed.

As many egg-allergic patients tolerate baked egg,

Leonard et al examined the role of baked egg in acquisition

of tolerance. They reported that 89% of egg-allergic patients

tolerated baked egg and, over time, 53% became regular

egg tolerant, compared to 26% of the control group. Those

who tolerated baked egg had lower egg white-sIgE levels.

Additionally, inclusion of baked egg in the diet appears to

hasten the acquisition of tolerance to regular egg.102

To date, two RCTs of egg OIT have been published. In 2012,

Burks et al reported successful desensitization in 55% of their

treatment group (n=40) and none of the placebo group (n=15).

After 22 months, this increased to 75% of the OIT group. After

discontinuation of OIT and avoidance of all egg products for

6–8 weeks, only 28% of the OIT group tolerated egg in an

OFC. This study demonstrates successful desensitization, but

long-term tolerance was achieved in less than one-third of

participants.103 Meglio et al published similar data for a group

of ten egg-allergic children, demonstrating that 80% were

desensitized over a 6-month period, but they did not examine

acquisition of tolerance.104 Tortajada-Girbés et al published

a prospective cohort trial of OIT involving 19 egg-allergic

children. Most participants (89.5%) reached the target dose of

egg and were able to tolerate egg in meals on a weekly basis.

There were no severe reactions during this trial, although two

participants withdrew as they experienced anaphylaxis with the

initial dose of OIT.105 Two small studies have examined a rush

protocol for the administration of egg OIT, demonstrating suc-

cessful desensitization over 5–12 days. Many participants had

reactions during OIT, but these were generally mild or moderate

in nature.106,107 Ojeda et al examined a home-based egg OIT pro-

tocol wherein participants were pretreated with antihistamines.

They found that 80.6% of subjects in the intention-to-treat

group achieved complete desensitization, tolerating the target

dose of one egg, while 3.2% reached incomplete tolerance and

16.2% achieved no tolerance. Children who were tolerant to

baked egg at baseline were more likely to achieve tolerance to

raw egg throughout the study.108

Two studies have examined SLIT for peach. After

6 months of SLIT with a Pru p 3 extract, the treatment group

tolerated higher doses of peach and had a smaller SPT

wheal size and increased specific IgG4.109 In a separate

study, García et al demonstrated that, among peach-allergic

individuals, the most commonly recognized antigen is Pru p

3 (83.3%). sIgE to Pru p 3 rose in both the SLIT treatment

group and the control group, but remained elevated only

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Optimal diagnosis and management of food allergies

in the treatment group. SPT wheal size decreased in the

treatment group.110

ConclusionWhile the mainstays of diagnosis and management in food

allergy remain relatively unchanged, there are several emerg-

ing modalities that offer exciting prospects for the future.

Though we rely heavily on SPT, component testing will likely

contribute to improved diagnostic accuracy. OFCs are safe

when performed appropriately and improve patients’ quality

of life. While management strategies are currently limited to

allergen avoidance and emergency treatment of accidental

exposures, immunotherapy trials offer great promise for

developing desensitization. Future studies exploring strate-

gies to induce tolerance are required. Improved diagnostic

capabilities and management techniques will revolutionize

food allergy diagnosis and management for physicians and

patients alike in years to come.

AcknowledgmentDr Ben-Shoshan is the recipient of the Fonds de recherche

du Québec Junior 1 award and the AllerGen NCE emerging

clinician scientist award.

DisclosureDr Ben-Shoshan is a consultant for Sanofi and Novartis. The

authors report no other conflicts of interest in this work.

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