allergen immunotherapy for ige … immunotherapy for ige-mediated food ... liam o’mahony21,...
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3ALLERGEN IMMUNOTHERAPY
FOR IgE-MEDIATED FOOD ALLERGY
A SYSTEMATIC REVIEW AND META-ANALYSIS
Supplementary materials
Ulugbek Nurmatov1, Sangeeta Dhami2, Stefania Arasi3,4, Giovanni Battista Pajno3, Montserrat Fernandez-Rivas5, Antonella Muraro6, Graham Roberts7,8, Cezmi Akdis9, Montserrat Alvaro-Lozano10, Kirsten
Beyer11,12, Carsten Bindslev-Jensen13, Wesley Burks14, George du Toit15, Motohiro Ebisawa16, Philippe Eigenmann17, Edward Knol18, Mika Makela19, Kari Christine Nadeau20, Liam O’Mahony21, Nikolaos
Papadopoulos22, Lars K Poulsen23, Cansin Sackesen24, Hugh Sampson25, Alexandra Santos26, Ronald van Ree27, Frans Timmermans28, Aziz Sheikh29
AFFILIATIONS1 Division of Population Medicine Neuadd Meirionnydd, School of Medicine, Cardiff University, Cardiff
2 Evidence-Based Health Care Ltd, Edinburgh, UK3 Department of Pediatrics, Allergy Unit, University of Messina, Messina, Italy
4 Molecular Allergology and Immunomodulation-Department of Pediatric Pneumology and Immunology, Charité Medical University, Berlin, Germany
5 Allergy Department, Hospital Clínico San Carlos, IdISSC, Madrid, Spain6 Department of Women and Child Health, Food Allergy Referral Centre Veneto Region, Padua General University Hospital,
Padua, Italy7 The David Hide Asthma and Allergy Research Centre, St Mary’s Hospital, Newport, Isle of WIght, UK
8 NIHR Biomedial Research Centre and Faculty of Medicine, University of Southampton, Southampton, UK9 Swiss Institute for Allergy and Asthma Research, Davos Platz, Switzerland
10 Paediatric Allergy and Clinical Immunology Section, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain11 Pediatric Pneumology and Immunology, Charité Universitätsmedizin, Berlin, Germany
12 Icahn School of Medicine at Mount Sinai, New York, NY, USA13 Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark
14 Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA15 Department of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, MRC & Asthma Centre in Allergic
Mechanisms of Asthma, King’s College London, St Thomas NHS Foundation Trust, London, UK16 Department of Allergy, Clinical Research Center for Allergy & Rheumatology, Sagamihara National Hospital, Sagamihara,
Kanagawa, Japan17 University Hospitals of Geneva and Medical School of the University of Geneva, Geneva, Switzerland
18 Department of Immunology and Department of Dermatology & Allergology, University Medical Center, Utrecht, The Netherlands
19 Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, Finland20 Department of Pediatrics, Division of Immunology, Allergy and Rheumatology, Stanford University, Stanford, CA, USA
21 Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland22 Department of Allergy, 2nd Pediatric Clinic, University of Athens, Athens, Greece23 Department of Allergy Clinic, Copenhagen University Hospital, Gentofte, Denmark
24 Department of Pediatric Allergist, Koç University Hospital, Istanbul, Turkey25 Mount Sinai Hospital, NY, USA
26 Department of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, King’s College London, Guy’s and St Thomas’ Hospital NHS Foundation Trust, London, UK
27 Departments of Experimental Immunology and of Otorhinolaryngology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
28 Nederlands Anafylaxis Netwerk – European Anaphylaxis Taskforce, Dordrecht, The Netherlands29 Asthma UK Centre for Applied Research, Usher Institute of Population Health Sciences and Informatics, The University of
Edinburgh, Edinburgh, UK
E-15EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Appendix 3.1 Search strategySearch strategy 1: MEDLINE, EMBASE
1 exp Food Hypersensitivity/
2 exp Milk Hypersensitivity/
3 exp Egg Hypersensitivity/
4 exp Peanut Hypersensitivity/
5 exp Tree nut Hypersensitivity/
6 exp Nut Hypersensitivity/
7 ((food or Oral Allergy Syndrome or milk or egg or peanut or arachis hypogaea or tree nut or hazelnut or brazil nut or walnut or chestnut or pistachio or almond or legumes or wheat or rice or soy or fish or seafood or shellfish or shrimp or lobster or crab or crawfish or kiwi or apple or peach or apricot or cherry or pear or plum or tomato or green pea or potato or carrot or parsley or celery or additives) adj3 (allerg* or hypersensitivit*)).mp. [mp=title, original title, abstract, name of substance word, subject heading word, unique identifier]
8 or/1-7
9 exp Desensitization, Immunologic/
10 exp Immunotherapy/
11 Desensiti?ation.mp.
12 Hyposensitisation.mp.
13 Allergy vaccination.mp.
14 Immunotherapy.mp.
15 Oral Immunotherapy.mp.
16 Oral desensiti?ation.mp.
17 Specific oral tolerance induction.mp.
18 Oral tolerance induction.mp.
19 Sublingual immunotherapy.mp.
20 Epicutaneous immunotherapy.mp.
21 Specific immunotherapy.mp.
22 Or/19-21
23 exp Intervention Studies/
24 Intervention Studies.mp.
25 Experimental stud*.mp.
26 exp Clinical Trial/
27 Trial.mp.
28 Clinical Trial.mp.
29 exp Controlled Clinical Trial/
30 Controlled Clinical Trial.mp.
31 Randomi?ed Controlled Trial.mp.
32 Quasi-randomi?ed trial.mp.
33 Non-randomi?ed trial.mp.
34 exp Placebos/
35 Placebos.mp.
36 exp Random Allocation/
37 Random Allocation.mp.
38 exp Double-Blind Method/
39 Double-Blind Method.mp.
40 Double-Blind design.mp.
41 exp Single-Blind Method/
42 Single-Blind Method.mp.
43 Single-Blind design.mp.
44 Triple-Blind Method.mp.
45 Random*.mp.
46 Exp.Case series/
47 (Case$ and series).tw.
48 Cost:.mp.
49 Cost effective:.mp.
50 Cost utility:.mp.
51 Exp Health care Costs/
52 (Costs and Costs Analysis).mp.
53 Economic evaluation*.mp.
54 ((cost effective* adj1 analys*) or cost minimi?ation analys* or cost benefit analys* or cost utility analys* or cost consequence analys* or finances).mp.
55 Or/23-54
56 8 and 22 and 55
E-16 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Search strategy 2: Cochrane Library, TRIP, CINAHL, ISI Web of Science, BIOSIS
(Food hypersensitivity or food allergy or Oral Allergy Syndrome or milk allergy or egg allergy or nut allergy or peanut allergy or arachis hypogaea allergy or tree nut allergy or hazelnut allergy or legumes allergy or wheat allergy or soy allergy or fish allergy or seafood allergy or shellfish allergy or kiwi allergy or apple allergy or peach allergy or additives hypersensitivity or additives allergy)
AND
(Immunologic, desensiti* or immunotherapy or hyposensitisation or oral immunotherapy or sublingual immunotherapy or subcutaneous immunotherapy or epicutaneous immunotherapy or intradermal
immunotherapy or intralymphatic immunotherapy or intranasal immunotherapy or specific immunotherapy or oral desensiti* or Specific Oral Tolerance Induction or Oral Tolerance Induction)
AND
(Intervention stud* or experimental stud* or trial or clinical trial* or controlled clinical trial or randomi* controlled trial or random allocation or single blind method or double blind method or triple blind method or random* or case series or economic evaluation* or cost effective* analys* or cost minimization analys* or cost benefit analys* or cost utility analys* or cost consequence analys* or finances)
E-17EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Study
Part
ecip
ants
ch
arac
teri
s-tic
s/ d
iagn
os-
tic c
rite
ria
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
RCT
(N
=2
5)
Anagnostou, 2014, UK
99
pts
(age
d 7
–16
yrs
) of
both
sex
es;
[pt a
lloca
tion:
O
IT (n
=4
9);
CG (n
=5
0);
pts
unde
r in
terv
entio
n:
OIT
(n =
49
); CG
(n=
47
)];
pts
anal
yzed
: O
IT (n
=3
9);
CG (n
=4
6)]
/
Hx
(+),
SPT
(+) t
o pe
anut
s, a
nd
DB
PCFC
(+).
cros
s-ov
er
RCT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
pean
ut1
st p
hase
: the
AG
und
erw
ent 2
6 w
ks
of p
eanu
t O
IT, a
nd t
he C
G 2
6 w
ks
of p
eanu
t av
oida
nce.
At
the
end
of
the
1st
pha
se (2
6 w
ks) a
ll pt
s w
ere
asse
ssed
by
DB
PCFC
. 2
nd p
hase
: pts
in t
he C
G s
till a
llerg
ic
to p
eanu
ts w
ere
offer
ed p
eanu
t O
IT,
with
a s
ubse
quen
t fu
rthe
r D
BPC
FC.
The
OIT
was
giv
en i
n da
ily d
oses
of
cha
ract
eris
ed l
ight
roa
st p
eanu
t flo
ur. F
irst
, the
re w
as a
gra
dual
up-
dosi
ng p
hase
with
2 w
k in
crem
ents
to
pro
tein
dos
es o
f 8
00
mg/
day,
an
d su
bseq
uent
ly
a m
aint
enan
ce
peri
od w
here
the
hig
hest
tol
erat
ed
dose
(with
a t
arge
t of
80
0 m
g/da
y)
was
tak
en d
aily
to
com
plet
e a
tota
l of
26
wks
OIT
.D
oses
wer
e: 2
mg,
5 m
g, 1
2·5
mg,
2
5 m
g, 5
0 m
g, 1
00
mg,
20
0 m
g,
40
0 m
g, a
nd 8
00
mg
of p
eanu
t pr
otei
n.
Dos
e in
crem
ents
to
ok
plac
e in
clin
ical
set
ting.
The
sam
e do
se w
as t
hen
give
n at
hom
e da
ily
for
2–3
wks
.
1st
pha
se:
OD
[=
ne
gativ
e pe
anut
D
BPC
FC
(1.4
g pr
otei
n)
at
6
mo]
: 6
2%
(2
4
of 3
9 p
ts;
95
%
CI 4
5–7
8) i
n th
e A
G a
nd n
one
of
the
CG (
0 o
f 4
6;
95
% C
I 0
–9;
p <
0·0
01
). 8
4%
(9
5%
CI 7
0–9
3)
of A
G t
oler
ated
da
ily
inge
stio
n of
0
.8g
prot
ein
(~
5
pean
uts)
. M
edia
n in
crea
se
in p
eanu
t thr
esh-
old
after
O
IT:
13
45
mg
(ran
ge
45
–14
00
; p
<
0·0
01
) or
25
.5
times
(r
ange
1
·82
–28
0;
p <
0
·00
1).
Afte
r th
e 2
nd
phas
e,
54
%
(95
%
CI
35
–72
) to
ler-
ated
1
40
0
mg
chal
leng
e (~
10
pe
anut
s)
and
91
%
(95
%
CI
79
–98
) to
lera
t-ed
da
ily
inge
s-tio
n of
80
0 m
g pr
otei
n.
Stat
is-
tical
ly
sign
if-ic
ant
im-
prov
e-m
ent
after
O
IT
(me-
dian
ch
ange
: 1
·61
; p
<
0·0
01
) in
DR
-Q
oL
scor
e as
-se
ssed
by
FA
Q-
LQ-P
F.
Whe
eze
after
0·4
1%
of
dos
es (
21
pts
). I.m
. E w
as u
sed
af-
ter
0·0
1%
of
dos-
es (
1 p
t).
Ove
rall,
4
pts
with
drew
for
fr
eque
nt A
Es:
2 i
n th
e A
G i
n th
e 1
st
phas
e an
d 2
in t
he
2nd
pha
se.
GI S
x w
ere,
col
-le
ctiv
ely,
th
e m
ost
com
-m
on (
31
pts
na
usea
; 3
1
pts
vom
iting
; 1
dia
rrho
ea),
then
or
al
prur
itus
after
6
.3%
of
dos-
es (7
6 p
ts).
Tabl
e S1
Det
aile
d ch
arac
teri
stic
s of
incl
uded
stu
dies
(n=
31
)
App
endi
x 3
.2
E-18 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Burks, 2012, USA
55
chi
ldre
n (a
ged
5-
11
yr
s, m
edia
n ag
e 7
yrs)
ra
ndom
ized
in
: AG
(n=
4
0) a
nd p
la-
cebo
gro
up
(n=
15
) / H
x (+
); sI
gE le
vel
> 5
kU
/l (≥
6
yrs)
, or
> 1
2
kU/l
(<5
yr
old)
DB
P-CR
CTO
IT v
s pl
aceb
oeg
g (D
EW)D
ose
esca
latio
n (c
linic
al r
esea
rch
set-
ting)
, bu
ild-u
p,
and
mai
nten
ance
ph
ases
unt
il th
e ch
alle
nge
at 1
0 m
o (5
g of
DEW
) w
ere
in D
BPC
RT.
Ope
n la
bel t
here
after
. Pla
cebo
the
n di
scon
-tin
ued,
OIT
gro
up o
n m
aint
enan
ce u
n-til
22
mo.
Child
ren
who
suc
cess
fully
pas
sed
the
10
g O
FC a
t 2
2 m
o di
scon
tinue
d O
IT
and
avoi
ded
all e
gg c
onsu
mpt
ion
until
1
0 g
(+
who
le c
ooke
d eg
g) O
FC a
t 2
4
mo,
to
test
for
sust
aine
d ur
espo
nsiv
e-ne
ss. C
hild
ren
who
pas
sed
this
OFC
at
24
mo
wer
e pl
aced
on
a di
et w
ith a
d li-
bitu
m e
gg c
onsu
mpt
ion
and
wer
e ev
al-
uate
d fo
r con
tinua
tion
of s
usta
ined
un-
resp
onsi
vene
ss a
t 30
mo
and
36
mo.
[D
ose
esca
latio
n: 1
st d
ose
0.1
mg
DEW
do
uble
d ev
ery
30
min
utes
up
to 5
0
mg.
The
max
imum
tol
erat
ed s
ingl
e do
se (m
inim
um d
ose
of 3
mg
of D
EW)
was
the
star
ting
dose
for
the
build
-up
phas
e to
be
inge
sted
dai
ly a
t ho
me.
Fo
r pt
s w
hose
max
imal
Day
1 d
ose
was
les
s th
an 5
0 m
g, d
oses
wer
e do
uble
d ev
ery
2 w
eeks
up
to 5
0 m
g.
Afte
r 5
0 m
g, d
osin
g w
as in
crea
sed
to
75
mg,
and
the
n do
sing
incr
ease
d by
2
5%
unt
il 2
g o
f D
EW w
as r
each
ed.
The
dose
ach
ieve
d at
10
mo
was
con
-si
dere
d th
e m
aint
enan
ce d
ose.
Pts
w
ho d
id n
ot r
each
30
6 m
g by
10
mo
wer
e di
scon
tinue
d fr
om d
osin
g bu
t w
ere
incl
uded
in
the
endp
oint
ana
ly-
sis.
Afte
r re
achi
ng th
eir
high
est b
uild
-up
dos
e (m
axim
um 2
g),
pts
cont
in-
ued
this
dos
e da
ily f
or a
t le
ast
2 m
o be
fore
the
mon
th 1
0 O
FC a
nd e
gg O
IT
pts
cont
inue
d m
aint
enan
ce
dosi
ng
thro
ugh
22
mo.
Per
pro
toco
l, su
bjec
ts
not r
each
ing
a m
aint
enan
ce d
ose
of 2
g
by 1
0 m
o w
ere
allo
wed
to
esca
late
to
2 g
afte
r th
e 1
0 m
onth
OFC
.]
Afte
r 1
0 m
o of
th
erap
y,
none
of
the
chi
ldre
n w
ho
rece
ived
pl
aceb
o an
d 5
5%
of
thos
e w
ho
rece
ived
O
IT p
asse
d th
e O
FC a
nd w
ere
cons
ider
ed
to
be
dese
nsi-
tized
. A
fter
22
m
o,
75
%
of
child
ren
in t
he
OIT
gro
up w
ere
dese
nsiti
zed.
In t
he O
IT g
roup
, 2
8%
(1
1
of
40
ch
ildre
n)
pass
ed
the
OFC
at
2
4
mo
and
wer
e co
nsid
ered
to
ha
ve s
usta
ined
un
resp
onsi
ve-
ness
. At 3
0 m
o an
d 3
6 m
o, a
ll ch
ildre
n w
ho
had
pass
ed t
he
OFC
at
24
mo
wer
e co
nsum
-in
g H
E.
AEs
, 2
5.0
%
of
11
,86
0
dose
s of
OIT
w
ith
egg
and
3.9
% o
f 4
01
8
dose
s of
pla
cebo
.R
es
pir
ato
ry
&
skin
A
Es:
3.2
%
of
40
18
pl
a-ce
bo
dose
s,
12
.2%
of
1
18
60
O
IT
dose
s.O
ral
or
phar
-yn
geal
A
Es:
78
%
of
OIT
do
ses,
2
0%
of
pl
aceb
o do
ses
(p
<
0.0
01
). A
fter
10
m
o,
the
rate
of
Sx i
n th
e O
IT g
roup
d
ec
rea
se
d to
8
.3%
of
1
5,8
15
dos
-es
.
Tabl
e S1
Con
tinue
d
E-19EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Caminiti, 2009, Italy
13
chi
ldre
n (8
mal
e,
aged
5-
10
yr
s, m
ean
age
8yr
s):
AG
(n=
10
); pl
aceb
o (s
oy fo
rmu-
la, n
=3
) /
Hx
(+),
SPT
(+),
SpIg
E (+
), D
BP-
CFC
(+)
RCT
(D
B-
PCR
T fo
r 6
pt
s;
open
fa
sh-
ion
7
pts)
OIT
vs
plac
ebo
cow
‘ s m
ilkTh
e de
sens
itiza
tion
sche
dule
sta
rt-
ed w
ith o
ne d
rop
of w
hole
CM
di-
lute
d 1
:25
eve
ry w
eek,
the
n do
u-bl
ed w
eekl
y un
til t
he 1
8th
wee
k to
ac
hiev
e an
int
ake
of 2
00
ml i
n ≈
4
mo.
All
dose
s w
ere
adm
inis
tere
d at
the
cl
inic
und
er m
edic
al s
uper
visi
on.
In t
he A
G,
7 c
hil-
dren
ac
hiev
ed
the
max
imum
do
se
of
20
0
ml
of m
ilk;
in 2
pt
s O
D
faile
d,
beca
use
of
se-
vere
A
Es;
1
pt
achi
eved
a p
ar-
tial
OD
(6
4
ml
of
milk
). Th
e 3
co
ntro
l ch
ildre
n re
ceiv
ing
plac
e-bo
st
ill
show
ed
a po
sitiv
e O
FC
at t
he e
nd o
f the
st
udy.
1 c
hild
in
the
dou-
ble-
blin
d gr
oup
stop
ped
the
OD
as
with
4 m
l of C
M h
ad
seve
re a
naph
ylax
is
(with
sho
ck)
trea
t-ed
with
i.m
. E;
AH
; i.v
. CS
and
grad
ual-
ly re
cove
red.
1
pt
in
th
e op
en
grou
p w
ith
4
ml
of
CM
had
R,
A,
gene
raliz
ed U
, an
d la
ryng
eal
edem
a;
he r
ecei
ved
i.m.
E an
d CS
; or
al
AH
; in
hale
d sa
lbut
amol
an
d pr
ompt
ly
re-
cove
red.
1
pt
achi
eved
a
part
ial
tole
ranc
e be
caus
e w
ith
the
dose
of
64
ml s
he
deve
lope
d U
, an
-gi
oede
ma,
co
ugh;
i.m
. A
H
and
CS
wer
e in
trod
uced
.
1
pt
in
the
doub
le-b
lind
grou
p an
d 2
pts
in
the
open
st
udy
grou
p ha
d th
roat
pr
u-ri
tis,
gritt
y ey
es,
wat
ery
eyes
, ab
-do
min
al p
ain,
tr
ansi
ent
er-
ythe
ma
(fac
e an
d ha
nds)
; no
m
edic
a-tio
n ha
s be
en
take
n
Tabl
e S1
Con
tinue
d
E-20 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Caminiti, 2015, Italy
31
chi
ldre
n of
bot
h se
xes
(age
d 4
-11
yrs
) ra
ndom
ized
to
OIT
with
D
EW (n
= 1
7)
or p
lace
bo
(n =
14
). O
f the
17
ac
tive
pts
(1
drop
out)
, 16
ac
hiev
ed O
D
and
star
ted
the
6-m
onth
eg
g-co
ntai
n-in
g di
et. /
Hx
(+),
SPT
(+)
and
sIgE
(+),
DB
PCFC
(+).
Non
e of
the
child
ren
had
prev
ious
ly
cons
umed
ba
ked
eggs
.
DB
P-CR
TO
IT v
s pl
aceb
oeg
g (D
EW)
The
OIT
pro
cedu
re c
onsi
sted
of w
eek-
ly
adm
inis
trat
ion,
at
th
e ho
spita
l cl
inic
, of i
ncre
asin
g do
sage
s of
DEW
, di
lute
d in
ste
rile
sal
ine,
sta
rtin
g w
ith
0.1
mg.
The
dos
e w
as d
oubl
ed e
very
w
k un
til w
k 1
6, t
o ac
hiev
e a
cum
ula-
tive
dose
of
4 g
in a
ppro
xim
atel
y 4
m
o. T
he p
lace
bo (c
orn
flour
, ind
istin
-gu
isha
ble
from
act
ive)
was
adm
inis
-te
red
follo
win
g th
e sa
me
prot
ocol
.
Of
the
17
ac-
tive
pts
(1
drop
out)
, 1
6
achi
eved
O
D
and
star
ted
the
6-m
onth
eg
g-co
ntai
ning
di
et.
Afte
r 3-m
onth
of
HE
avoi
danc
e,
31
% o
f the
16
pt
s th
at
have
ac
hiev
ed
OD
an
d pe
rfor
med
th
e 6
-mon
th
egg-
cont
aini
ng
diet
re
mai
ned
tole
rant
. In
th
e co
ntro
l gr
oup,
on
ly
1
pass
ed th
e fin
al
OFC
.
D
urin
g O
D 1
pt f
aile
d O
IT
for
SR
(U,
thro
at p
ruri
tus,
R,
A,
vom
iting
). D
ur-
ing
HE-
cont
aini
ng
diet
: 1
pt
pres
ent-
ed
U,
abdo
min
al
pain
afte
r ex
erci
se
(1 c
ooke
d H
E) a
nd
anot
her
whe
ezin
g an
d co
ugh
duri
ng
uppe
r re
spira
tory
in
fect
ion
(1 c
ooke
d H
E). B
oth
wer
e to
l-er
ant
after
3 m
o of
H
E co
ntai
ning
die
t di
scon
tinua
tion
Dur
ing
OD
1
pt
pr
esen
t-ed
er
ythe
ma
of
face
an
d ha
nds
(1.5
m
g D
EW)
and
anot
her
ab-
dom
inal
pa
in
and
diar
rhea
(3
mg
DEW
).
Tabl
e S1
Con
tinue
d
E-21EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Dello Iacono, 2013, Italy
20
chi
ldre
n (a
ged
5 -
11
yr
s, m
edi-
an a
ge 7
. 7
yrs;
mal
e 5
0%
) wer
e en
rolle
d:
OIT
(n =
10
); ro
utin
e ca
re
(n =
10
) /
Incl
usio
n cr
i-te
ria:
i) ≥
1
anap
hyla
ctic
re
actio
n aft
er
acci
dent
al
egg
expo
sure
w
ithin
12
mo
of p
re-e
nrol
-m
ent;
(ii) p
re-
viou
s SP
T/Ig
E po
sitiv
e fo
r eg
g (ii
i) a
posi
tive
DB
-PC
FC a
t ≤0
.9
ml o
f raw
egg
em
ulsi
on.
open
R
CTO
IT v
s ro
utin
e ca
re
(foo
d av
oid-
ance
)
(raw
) egg
Initi
al d
ay e
scal
atio
n ph
ase:
1 d
rop
of
undi
lute
d ra
w H
E em
ulsi
on (
0.0
15
m
l) fla
vour
ed w
ith v
anill
a an
d ca
cao
in d
ay h
ospi
tal;
Day
2-7
at h
ome
1 d
rop.
B
uild
-up
phas
e:
OIT
co
ntin
ued
at
hom
e w
ith g
radu
ally
incr
easi
ng d
os-
es m
ixed
by
the
pare
nts
in th
e ch
ild’s
br
eakf
ast
(cow
’s m
ilk, s
oym
ilk, f
ruit
juic
e or
oth
er) a
nd 5
dou
blin
g do
ses
in d
ay h
ospi
tal u
p to
40
ml (
mai
nte-
nanc
e do
se) o
ver
abou
t 6 m
o.
Afte
r 6
m
o of
O
IT,
no
child
co
uld
tole
rate
4
0
ml
of
raw
H
E em
ulsi
on
in
a si
ngle
do
se
as
none
re
ache
d th
e fin
al
dose
of
th
e pr
otoc
ol;
9/1
0
(90
%)
achi
eved
pa
r-tia
l O
D
(10
-4
0m
l),
and
1/1
0
(10
%)
was
abl
e to
in-
gest
onl
y 5
ml.
Non
e co
ntro
l pt
s ac
hiev
ed
tole
ranc
e.
The
med
ian
max
-im
al
tole
rat-
ed
dose
w
as
20
m
l (r
ange
: 5
–30
m
l) in
A
G a
nd 0
.45
ml
(ran
ge: 0
.22
5–
1.8
) in
CG
(p
<
0.0
00
1).
A
ll ch
ildre
n in
A
G
had
AEs
(5
3
AEs
), no
ne
re-
quir
ed
E.
In
CG,
5 A
Es i
n 4
/
10
pt
s.
AG
vs
CG 2
3
/ 5
3 v
s 0
/ 5
sk
in /
resp
ira-
tory
, 21
/ 5
3
vs 5
/ 5
ora
l/G
I. In
the
AG
re
lativ
e ri
sk
of
incu
rrin
g an
A
E:
4.9
6
(95
%
CI
=
3.3
0–7
.45
). H
owev
er,
no
sig
nif
ica
nt
diffe
renc
es i
n th
e se
veri
ty
of
AEs
be
-tw
een
AG
vs
CG.
Tabl
e S1
Con
tinue
d
E-22 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Dupont, 2010, France
19
chi
ldre
n [a
ged
10
m
onth
s to
7.7
yrs
(m
ean
± S
D,
3.8
2 ±
2
yrs)
] wer
e ra
ndom
ized
: O
IT (n
=1
0);
plac
ebo
(n =
9
) / In
clus
ion
crite
ria:
Hx
(+),
SPT
(+)
and
/ or
sIg
E (+
), O
FC (+
).
DB
P-CR
TEP
IT v
s pl
aceb
oco
w‘ s
milk
Trea
tmen
t co
nsis
ted
of
thre
e 4
8-
hour
app
licat
ions
of
the
epic
utan
e-ou
s de
vice
s (E
DS)
per
wk
(Via
skin
; D
BV
Tec
hnol
ogie
s SA
, Par
is, F
ranc
e)
for
3
mon
s to
th
e in
ters
capu
lar
area
. A
ctiv
e ED
S co
ntai
ned
1 m
g sk
imm
ed C
M p
owde
r. Pl
aceb
o co
n-ta
ined
1 m
g gl
ucos
e.
EPIT
tr
eatm
ent
tend
ed
to
in-
crea
se
the
cu-
mul
ativ
e to
l-er
ated
do
se
duri
ng
OFC
(C
TD)
in t
he A
G
[ fr
om a
mea
n ±
SD
of
1
.77
±
2
.98
m
L at
da
y 0
to
23
.61
±
2
8.6
1
mL
at d
ay 9
0 (
P =
.1
8)]
but
not
in
the
CG (
4.3
6 ±
5
.87
mL
at d
ay
0
vs
5.4
4
±
5.8
8 m
L at
day
9
0).
The
mea
n CT
D
incr
emen
t w
as
12
-fol
d in
th
e A
G v
s 8
% in
CG
(P =
0.1
3).
24
SR
s oc
curr
ed i
n th
e A
G a
nd 8
in th
e CG
, (r
espi
rato
ry/
ENT
diso
rder
s,
p 0
.9;
gast
roin
test
inal
dis
ord
ers
<.0
01
).
No
anap
hila
xis.
No
child
in
terr
upte
d tr
eatm
ent b
ecau
seof
an
AE,
and
non
e re
ceiv
ed
epin
eph-
rine
or
was
see
n at
th
e em
erge
ncy
depa
rtm
ent
or h
os-
pita
l.
Loca
l AEs
wer
e re
port
edfo
r 4
ch
ildre
n in
the
AG
and
2
in
th
e CG
(p
<.0
01
).
Enrique, 2005, Spain
23
adu
lts
(age
d 1
8 to
6
0, m
ean
age
29
.4) r
and-
omiz
ed in
to:
AG
(n=
12
) an
d pl
ace-
bo g
roup
(n
=1
1);
Hx
(+),
SPT
(+),
SpIg
E (+
), D
BPC
FC (+
)
DB
P-CR
TSL
IT
(sub
lin-
gual
-dis
-ch
arge
te
ch-
niqu
e) v
s pl
aceb
o
haze
lnut
A b
iolo
gica
lly s
tand
ardi
zed
haze
lnut
ex
trac
t, gr
aded
in
5 s
tren
gths
(F0
, F1
, F2
, F3
, FA
) in
glyc
eros
alin
e so
lu-
tion
was
use
d. R
ush
build
-up
phas
e A
ll do
ses
wer
e ad
min
istr
ated
in
a ho
spita
l se
ttin
g (3
09
dos
es)
and
was
co
mpl
eted
in
4
da
ys;
dose
s w
ere
adm
inis
tere
d at
1
5
min
ute.
M
axim
um d
ose
(4th
day
) co
ntai
ned
18
8.1
5 µ
g of
Cor
a 1
and
12
1.9
µg
of C
or a
8 (
equa
l to
25
dro
ps f
rom
th
e m
ost
conc
entr
ated
via
l). A
fter
the
build
-up
phas
e, a
ll pt
s fo
llow
ed
the
sam
e da
ily m
aint
enan
ce s
ched
-ul
e co
nsis
ting
of 5
dro
ps o
f th
e m
axim
um c
once
ntra
tion
perf
orm
ed
at h
ome
(11
57
dos
es).
Tota
l dos
es a
dmin
iste
red
14
66
.
Mea
n ha
zel-
nut
quan
ti-ty
pr
ovok
ing
obje
ctiv
e Sx
in
cr
ea
se
d fr
om
2.2
9
g to
1
1.5
6
g (P
=0
.02
) in
to
AG
vs
3
.49
g to
4.1
4g
(pla
-ce
bo;
NS)
. A
l-m
ost
50
%
of
pts
into
A
G
reac
hed
the
high
est
dose
(2
0 g
); 9
% i
n th
e CG
.
SRs
0.2
% (
3 A
Es/
14
66
dos
es);
they
oc
curr
ed
duri
ng
build
-up
phas
e an
d on
ly A
H w
ere
used
; 1
fac
ial U
occ
urre
d in
th
e CG
an
d 2
A
Es i
n 1
pt
of t
he
AG
(s
kin
prur
itis
and
dela
yed
U).
LRs:
im
me-
diat
e or
al
itchi
ng
wer
e ob
serv
ed
in
7.4
%
(10
9
rea
cti
on
s/
14
66
dos
es);
durin
g bu
ild-
up
phas
e,
4
pts
in t
he A
G:
ab
do
min
al
pain
se
vera
l ho
urs
after
th
e in
gest
ion
on 1
occ
asio
n ea
ch.
All
LRs
durin
g m
ain-
tena
nce
phas
e w
ere
also
ora
l itc
hing
, an
d al
l wer
e in
the
sa
me
pt.
Tabl
e S1
Con
tinue
d
E-23EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Escudero, 2015, Spain61
pts
[63
%
mal
e (7
3%
in
AG
and
5
2%
in C
G)
aged
5-
17
yr
s, (m
edia
n,
8 y
rs; I
QR
, 6
yrs)
] ran
d-om
ized
into
: O
IT g
roup
(n
=3
0) a
nd
CG (n
=3
1) /
H
x (+
), SP
T (+
), Sp
IgE
(+),
DB
PCFC
(+
)
RCT
OIT
vs
rout
ine
care
egg
Initi
al d
ay d
ose
esca
latio
n ph
ase:
in
1 d
ay a
dmin
istr
atio
n of
0.0
8,
0.2
, 0
.3, 0
.5, 1
, 2, 5
, 9, 1
7, 3
5, 7
0 a
nd
14
0 m
g of
EW
pro
tein
(cu
mul
ativ
e do
se 2
80
mg)
at
inte
rval
s of
20
m
inut
es.
Bui
ld-u
p ph
ase:
inc
reas
ing
dose
s of
0
.02
, 0
.3,
3,
14
, 6
8,
18
8,
35
2,
14
04
mg
and
28
08
mg
of E
W p
ro-
tein
on
a w
eekl
y ba
sis.
M
aint
enan
ce
phas
e,
cons
istin
g in
ea
ting
at
leas
t on
e un
derc
ooke
d eg
g (f
ried
egg
, sc
ram
bled
or
un-
derc
ooke
d om
elet
te)
com
puls
ory
ever
y 4
8 h
ours
. M
oreo
ver,
dur
ing
this
pha
se, t
he p
t co
uld
free
ly t
ake
any
othe
r fo
odst
uffs
cont
aini
ng ra
w,
cook
ed o
r he
ated
egg
(i.e
. can
dies
, sa
uces
and
ice
crea
m).
Afte
r 3
mo
of A
IT, c
hild
ren
who
com
-pl
eted
egg
-OIT
avo
ided
egg
for
1
mon
th.
At
4 m
o, b
oth
grou
ps u
n-de
rwen
t a
DB
PCFC
. O
ITG
pts
who
pa
ssed
thi
s ch
alle
nge
wer
e in
stru
ct-
ed to
add
egg
to th
eir d
iet a
d lib
itum
.
A
t 4
m
o,
37
%
(11
/30
) of
A
G
pts
pass
ed
the
DB
PCFC
, vs
3%
(1
/31
) in
CG
(9
5%
CI
for
the
diffe
renc
e in
the
re
spon
se
rate
, 1
4 t
o 5
1%
; P =
0
.00
3).
The
AG
pt
s (n
=1
4)
who
di
d no
t pa
ss D
B-
PCFC
at
4
m
o in
crea
sed
thei
r th
resh
old
mea
n do
se fr
om 1
00
.8
mg
EW
prot
ein
(SD
, 9
6.3
m
g)
at
base
line
to
48
1.3
m
g (S
D,
41
7.5
mg)
at
4
mo
(P =
0.0
02
). Th
e la
tter
w
as
sig
nif
ica
ntl
y hi
gher
th
an
in
CG (
mea
n 2
56
.2
mg,
SD
4
25
.3
mg)
(P
= 0
.02
). CG
pt
s sh
owed
a
non-
sign
ifica
nt
incr
ease
in
thei
r th
resh
old
from
ba
selin
e (m
ean
21
8.3
m
g,
SD
40
5.5
mg)
to
4
mo
(mea
n 2
56
.2
mg,
SD
4
25
.3
mg)
(P =
0.4
1).
E
trea
tmen
t on
ly i
n 1
pt
duri
ng b
uild
-up
ph
ase
(0.0
4%
of
all
AEs
)
14
5
AEs
du
ring
O
IT
in
70
%
(21
/30
) of
pt
s.
[n
(%)]
: 2
1
(14
.5%
) in
th
e in
i-tia
l-day
do
se
es
ca
lati
on
phas
e;
79
(
54
.5%
) in
bu
ild-u
p ph
ase;
an
d 4
5 (
31
%),
in
mai
nten
ance
ph
ase.
Th
ey
wer
e ov
er-
all
mild
un
-le
ss
1
case
. S
ym
pt
om
ty
pe [
n (%
)]:
Gen
eral
ized
U
(0
.3%
); R
3
2
(1.3
%);
Re
spir
ato
ry
Dis
tres
s 5
(0
.2%
); G
I 97
(4
%).
Tabl
e S1
Con
tinue
d
E-24 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Fernandez-Rivas, 2009, Spain
56
adu
lt pt
s (a
ged
18
-65
yr
s) ra
n-do
mis
ed in
to:
activ
e gr
oup
[(n=
37
) (a
Pru
p 3
qua
n-tifi
ed p
each
ex
trac
t)]
or p
lace
-bo
gro
up
[(n=
19
) (s
imila
r so
lutio
n w
ith-
out p
each
al
lerg
en)]
/
Hx
(+),
SPT
(+),
sIgE
(+),
DB
PCFC
(+)
DB
P-CR
TSL
IT v
s pl
aceb
o pe
ach
The
trea
tmen
t w
as a
dmin
iste
red
sub-
lingu
ally
(s
ublin
gual
-sw
allo
w
tech
-ni
que)
and
com
pris
ed 4
via
ls c
on-
tain
ing
0.4
, 2, 1
0 a
nd 5
0 µ
g/m
l of
Pru
p 3
or
plac
ebo.
Rus
h bu
ild-u
p ph
ase
in h
ospi
tal
(Tot
al d
aily
dos
e of
Pru
p 3
in µ
g): 1
st d
ay –
3 d
oses
(0
.22
µg)
of
Pru
p 3
; 2
nd d
ay –
3
dose
s (1
.12
µg)
; 3
rd d
ay –
3 d
os-
es (
5.6
0 µ
g);
4th
day
– 3
dos
es
(28
.0 µ
g); 5
th d
ay –
1 d
ose
(50
µg)
. H
ome
mai
nten
ance
(6
mo)
Mon
day,
W
edne
sday
and
Fri
day
1 d
ose
of P
ru
p 3
pea
ch e
xtra
ct (1
0.0
µg)
; pts
vis
-ite
d th
e cl
inic
s on
ce a
mon
th.
DB
PCFC
w
ith
peac
h (a
fter
6 m
o):
the
AG
to
lera
ted
a si
gn
ific
an
tly
high
er a
mou
nt
of p
each
(3
to
9 f
old,
nee
ded
to in
duce
LR
or
SR, r
espe
ctiv
e-ly
); in
ter
grou
p di
ffere
nces
at
T6
mo
for
SR
wer
e al
mos
t s
ign
ific
an
t (L
og R
ank
test
, P=
0.0
6).
No
sign
ifica
nt
chan
ges
wer
e ob
serv
ed w
ith-
in C
G.
Act
ive
grou
p:
16
SR
s:
14
in
th
e bu
ild-u
p ph
ase
(6
pts
skin
AEs
, 1 R
C,
7 G
I co
mpl
aint
s)];
2 d
urin
g th
e ho
s-pi
tal
mai
nten
ance
w
k [1
RC
and
1 G
I co
mpl
aint
s].
All
SRs
wer
e m
ild a
nd
subs
ided
ei
ther
sp
onta
neou
sly
or
with
ora
l A
H,
ant-
acid
s an
d/or
om
e-pr
azol
e.
Plac
ebo
grou
p:
3
SRs
1 in
the
bui
ld-
up
phas
e (c
uta-
neou
s itc
hing
), an
d 2
in
the
first
m
aint
enan
ce w
k (1
an
gioe
dem
a an
d 1
di
arrh
ea)
From
a
tota
l of
14
80
AEs
re
co
rde
d,
13
56
w
ere
asse
ssed
by
th
e in
vest
iga-
tors
as
prob
-ab
ly a
nd/
or
poss
ibly
re
-la
ted
to
the
tre
atm
en
t:
13
44
in
the
AG
, an
d 1
2
in t
he P
G (
P <
.00
01
).N
o se
riou
s A
Es
wer
e re
port
-ed
du
ring
th
e tr
ial.
AG
: LR
s 9
8.8
%
(n=
13
28
);
mos
tly
dur-
ing
build
-up
phas
e an
d th
e 1
st m
ain-
tena
nce
wk
(P=
0.0
14
);
94
.9
%
(n=
12
60
) lo
cate
d on
th
e or
opha
r-yn
x, o
ther
s G
I co
mpl
aint
s.
Tabl
e S1
Con
tinue
d
E-25EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Fleischer, 2012, USA
40
sub
ject
s (m
ale
68
%)
aged
12
to
37
yrs
(m
edia
n ag
e,
15
yrs)
rand
-om
ized
into
A
G (n
= 2
0)
or p
lace
bo (n
=
20
). /
Hx
(+),
pean
ut
SPT
(+)
(whe
al d
iam
-et
er >
3m
m)
or d
etec
tabl
e pe
anut
-sI-
gE (>
0.3
5
kUA
/L),
DB
PCFC
(+)
(obj
ectiv
e al
lerg
ic S
x at
a
cum
ulat
ive
dose
of <
2
g of
pea
nut
pow
der)
.
DB
P-CR
T,
mul
ti-ce
ntre
tr
ial
SLIT
vs
plac
ebo
pean
utPh
ase
1 B
uild
-up
phas
e: D
osin
g st
art-
ed a
t 0
.00
01
65
µg
of p
eanu
t pr
o-te
in o
r pl
aceb
o es
cala
tion
thro
ugh
66
0
µg
occu
rred
ev
ery
2
wks
, 6
60
µg a
ttai
ned
at 1
2 w
ks.
3 d
os-
es a
ttem
pted
at
a m
inim
al i
nter
val
of 3
0 m
inut
es. I
f pt
s fa
iled
3-
dose
es
cala
tions
afte
r 3
con
secu
tive
bi-
wee
kly
atte
mpt
s, 1
- or
2-d
ose
bi-
wee
kly
esca
latio
ns
wer
e al
low
ed
subs
eque
ntly
. A
fter
each
obs
erve
d do
se, p
ts c
ontin
ued
the
sam
e da
ily
dose
at
hom
e fo
r 2
wks
. Afte
r 6
60
µg
was
ach
ieve
d, s
ingl
e do
se i
n-cr
ease
s oc
curr
ed, f
ollo
wed
by
2 w
ks
of m
aint
enan
ce t
hera
py o
f 1
,38
6
µg/d
. Pt
s to
ok a
min
imum
dos
e of
1
65
µg
and
a m
axim
um
mai
nte-
nanc
e do
se o
f 1
38
6 µ
g of
pea
nut
prot
ein
or p
lace
bo (
42
0µl
) at
hom
e on
a d
aily
bas
is fo
r th
e m
aint
enan
ce
peri
od u
ntil
the
wk
44
.U
nblin
ding
5
-g
DB
PCFC
. A
fter
un-
blin
ding
, pts
rec
eivi
ng a
ctiv
e pe
anut
SL
IT c
ontin
ued
on m
aint
enan
ce d
os-
ing
with
a 1
0-g
OFC
afte
r ap
prox
i-m
atel
y 1
yr
of m
aint
enan
ce th
erap
y.Ph
ase
2 P
lace
bo p
ts c
ross
ed o
ver
to
activ
e pe
anut
SLI
T an
d w
ere
esca
lat-
ed to
a m
axim
um m
aint
enan
ce d
ose
of 3
69
6m
g (1
12
0µl
). A
5g
cros
so-
ver O
FC w
as p
erfo
rmed
afte
r 44
wks
of
SLI
T.
Wee
k 44
Unb
lindi
ng
OFC
). Pt
s su
cces
s-fu
lly
cons
umin
g 5
g or
at
le
ast
10-fo
ld
mor
e pe
anut
po
wde
r th
an t
he b
asel
ine
OFC
th
resh
old
wer
e co
nsid
ered
re
spon
ders
: 70
%
(n=1
4) in
the
AG
vs
15%
in th
e CG
(p
<0.0
01).
The
med
ian
suc-
cess
fully
co
n-su
med
dos
e (S
CD)
at W
eek
44 w
as
sign
ifica
ntly
hi
gh-
er t
han
the
base
-lin
e O
FC
for
AG
pt
s (3
71 v
s 21
m
g,
resp
ectiv
ely;
P
<.01
) but
not
for
CG p
ts (1
46 vs
71
m
g,
resp
ectiv
ely;
P
=.14
). H
owev
er,
the
med
ian
SCD
aft
er
44
wks
of
th
erap
y w
as
not
sign
ifica
ntly
di
f-fe
rent
be
twee
n tr
eatm
ent
grou
ps
(P=0
.16)
.A
ll W
eek
44
re-
spon
ders
stil
l be
-in
g fo
llow
ed w
ere
Wee
k 68
resp
ond-
ers.
The
med
ian
SCD
incr
ease
d to
99
6 m
g, a
nd t
his
was
si
gnifi
cant
-ly
hig
her
than
at
Wk
44 (
P =.
05)
and
base
line
(P
=.00
9)
Onl
y 1
out
of
12
7
AEs
req
uire
d E
and
oral
ant
ihis
tam
ine.
Onl
y 1
27
(1
.1%
) of
1
1,8
54
to
-ta
l do
ses
re-
quire
d tr
eat-
men
t du
ring
th
e 1
st p
hase
: 1
25
(1
.1%
), or
al A
H o
nly;
1
(0
.01
%),
albu
tero
l onl
y.
Tabl
e S1
Con
tinue
d
E-26 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Fuentes-Aparicio, 2013, Spain
72
pts
(age
d 4
-15
yrs
) ra
ndom
ly
assi
gned
to
OIT
(n =
40
) or
elim
inat
ion
diet
(n =
32
) /
Hx
(+),
SPT
(+),
sIgE
(+),
DB
PCFC
(+)
RCT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
egg
[pow
dere
d pa
steu
r-is
ed e
gg]
On
the
1st
day
, fra
ctio
nate
d do
ses
of
pow
dere
d pa
steu
rize
d eg
g m
ixed
w
ith j
uice
or
milk
shak
es w
ere
ad-
min
iste
red
until
rea
chin
g 3
1 m
g of
eg
g, b
egin
ning
with
1 m
g an
d co
n-tin
uing
with
3, 9
, and
18
mg
at 3
0
min
int
erva
ls.
On
the
2nd
day
, 3
0
mg
in o
ne s
ingl
e do
se w
as a
dmin
-is
tere
d, w
ith t
he t
reat
men
t co
ntin
-ui
ng a
t ho
me
at t
his
sam
e do
sage
. Su
bseq
uent
ly,
wee
kly
incr
ease
s w
ere
mad
e in
the
clin
ic u
ntil
10
g o
f po
wde
red
egg,
the
equi
vale
nt o
f one
eg
g, w
as r
each
ed.
The
proc
edur
e’s
aver
age
dura
tion
was
10
wks
(ran
ge
4-2
8 w
ks).
Then
, 2 e
ggs/
wee
k w
ere
adm
inis
trat
ed a
t hom
e.
A m
onth
afte
r fin
ishi
ng t
he t
reat
men
t th
e pt
s w
ere
cont
acte
d by
tele
phon
e an
d if
they
had
goo
d O
D t
hey
wer
e re
com
men
ded
a no
rmal
(no
n eg
g-fr
ee)
diet
. The
pts
had
follo
w-u
ps a
t th
e cl
inic
6 a
nd 1
2 m
o aft
er a
chie
v-in
g O
D. A
n O
FC w
ith r
aw e
gg w
hite
in
the
OIT
gro
up a
fter
6 m
o fr
om th
e en
d of
OIT
.
37
ou
t of
4
0
child
ren
fin-
ishe
d th
e O
IT,
2
pts
wer
e w
ith
dr
aw
n fr
om t
he s
tudy
du
e to
rep
eat-
ed G
I Sx
dose
s.
Ano
ther
pt
was
w
ithdr
awn
with
5
00
mg
due
to
susp
ecte
d an
d la
ter
confi
rmed
e
osi
no
ph
ilic
o
eso
phag
itis
. N
o w
ithdr
awal
s in
the
CG
. Afte
r 6
mo
from
the
en
d of
OIT
, 3
2
pts
(92
.5%
) in
th
e A
G p
asse
d O
FC
with
ra
w
egg
whi
te
vs
21
.8%
in
th
e CG
(n
atur
al
reso
lutio
n).
3
pts
out
of 4
0 in
the
AG
wer
e w
ithdr
awn
from
th
e pr
otoc
ol
for
pers
iste
nt
GI
Sx.
Dur
ing
OIT
, 2
1
pts
(52
.5%
) pr
e-se
nted
AEs
. In
13
(6
1.9
0%
), th
e A
Es
wer
e m
oder
ate-
se
vere
, res
ultin
g in
do
ses
havi
ng t
o be
re
peat
ed,
and
in 5
ca
ses
E w
as n
eed-
ed. D
urin
g th
e O
FC,
AEs
wer
e se
vere
in
9 (
33
.4%
) an
d in
1
0
(40
%)
and
E us
ed in
6 (
22
.3%
) an
d 7
(28
%) i
n th
e A
G a
nd C
G, r
espe
c-tiv
ely.
Dur
ing
OIT
, in
8
pts
in
the
OIT
gro
up t
he
AEs
wer
e m
ild
and
requ
ired
no
tre
atm
ent.
Dur
ing
the
OFC
, A
Es
wer
e m
ild in
6
(22
.3%
) an
d 4
pts
(1
6%
) an
d m
od-
erat
e in
1
2
(44
.5%
) an
d in
11
(4
4%
) in
the
AG
and
CG
, re
spec
-tiv
ely.
Tabl
e S1
Con
tinue
d
E-27EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Kim, 2011, USA
18
chi
ldre
n (a
ged
1 -
11
yr
s) w
ere
rand
omiz
ed
into
: AG
(n
=1
1) a
nd C
G
(n=
7).
/ H
x (+
), sI
gE >
7
kU/L
DB
P-CR
TSL
IT v
s pl
aceb
o pe
anut
All
obse
rved
dos
ing
was
per
form
ed in
th
e ho
spita
l. A
G r
ecei
ved
dilu
tions
of c
rude
pea
nut
extr
act
(1:2
0 w
t/vo
l) di
ssol
ved
in
0.2
% p
heno
l and
50
% to
55
% g
lyc-
erin
ated
sal
ine
(max
pea
nut c
once
n-tr
atio
n 5
00
0 µ
g/m
l. CG
rec
eive
d a
glyc
erin
ated
sal
ine
solu
tion
+ p
he-
nol
with
car
amel
col
orin
g (d
oses
1
to 8
pum
ps (5
0 µ
L pe
r pu
mp)
.Th
e fir
st d
ay t
he s
tart
ing
dose
was
0
.25
µg
of p
eanu
t pr
otei
n (1
pum
p of
1:1
00
0 d
ilutio
n).
Subj
ects
the
n re
turn
ed f
or 1
3 b
iwee
kly
obse
rved
do
se-e
scal
atio
n vi
sits
. A
fter
each
ob
serv
ed d
ose
esca
latio
n, p
ts c
on-
tinue
d th
e sa
me
dose
dai
ly a
t ho
me
for
2 w
ks.
Whe
n th
e m
aint
enan
ce
dose
rea
ched
20
00
- µg
of
pean
ut
prot
ein
(8 p
umps
of
1:1
sto
ck d
i-lu
tion)
, pt
s co
ntin
ued
daily
mai
nte-
nanc
e do
sing
at
hom
e fo
r ap
prox
i-m
atel
y 6
mo.
At
the
12
- m
onth
- D
BP-
CFC,
in
AG
, al
l 1
1
pts
had
a si
gnifi
cant
in
-cr
ease
in
reac
-tio
n th
resh
old
after
saf
ely
in-
gest
ing
a m
edi-
an
cum
ulat
ive
dose
of
17
10
m
g of
pe
anut
pr
otei
n (a
20
-fo
ld
grea
ter
amou
nt o
f pea
-nu
t pr
otei
n an
d ap
prox
imat
ely
equi
vale
nt
to
6-7
pe
anut
s).
In C
G, t
he 7
pts
on
ly s
afel
y in
-ge
sted
a m
edi-
an
cum
ulat
ive
dose
of
85
mg
(<1
pe
anut
), (O
D: A
G v
s CG
, p=
0.0
11
)
One
(0
.02
%)
pt
had
mild
w
heez
-in
g w
hich
req
uire
d al
bute
rol.
No
E re
-qu
ired
fo
r w
hole
st
udy.
AEs
w
ere
re-
port
ed
with
1
1.5
%
of
pean
ut d
oses
an
d 8
.6%
of
plac
ebo
dos-
es.
Skin
Sx
: 0
.6%
in
AG
, 6
.5%
in
CG
. In
AG
mos
t of
th
e Sx
w
ere
tra
ns
ien
t o
rop
ha
ryn
-ge
al
itch-
ing
(9.3
%),
whe
reas
sk
in
itchi
ng
was
m
ost
com
-m
on
in
CG
(6.5
%).
Of
the
41
82
ac
tive
pea-
nut
dose
s,
11
(0
.26
%)
hom
e do
ses
requ
ired
AH
.N
o pl
aceb
o do
ses
re-
quir
ed
AH
or
al
bute
rol
trea
tmen
t.
Tabl
e S1
Con
tinue
d
E-28 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Lee, 2013, Korea
31
infa
nts
(7 to
12
mo
old)
rand
omly
as
sign
ed to
O
IT (n
= 1
6)
or e
limin
a-tio
n di
et (n
=
15
) and
ev
alua
ted
6
mo
late
r. 2
6
pts
conc
lud-
ed th
e st
udy
[OIT
(n =
14
); ro
utin
e ca
re
(n=
12
)] /
Hx
(+),
SPT
(+)
to C
M, a
nd
DB
PCFC
(+).
RCT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
cow
‘ s m
ilkTh
e in
itial
bui
ld-u
p ph
ase
took
pla
ce
in t
he h
ospi
tal,
with
a ra
pid
incr
ease
in
CM
do
sage
ev
ery
30
m
inut
es
from
0.5
ml t
o a
max
imum
of
2 m
L of
CM
. Th
erea
fter,
pts
beg
an h
ome
dosi
ng w
ith 2
mL
of C
M. D
oses
wer
e in
crea
sed
at h
ome
ever
y w
k or
de-
crea
sed
base
d on
the
freq
uenc
y an
d se
veri
ty o
f A
Es (
min
imum
dur
atio
n:
22
wks
) up
to 2
00
ml.
Fam
ilies
con
-ne
cted
to
the
2 g
roup
s w
ere
con-
tact
ed b
y re
gula
r cl
inic
vis
its a
nd
inst
ruct
ed to
pho
ne th
e st
udy
phys
i-ci
ans
in th
e ev
ent o
f any
AEs
.
14
of
1
6
pts
rece
ivin
g O
IT
coul
d ac
cept
da
ily
dose
s of
20
0 m
L of
CM
, whe
reas
all
but
3 d
ropo
ut
pts
rece
ivin
g th
e el
imin
a-tio
n di
et
still
sh
owed
alle
rgic
Sx
at
th
e fo
l-lo
w-u
p O
FC.
Onl
y 2
pts
, bo
th i
n th
e O
IT g
roup
, pre
-se
nted
sev
ere
AEs
du
ring
th
e in
itial
bu
ild-u
p ph
ase,
w
hich
re
sulte
d in
th
eir
early
w
ith-
draw
al.
12
of
14
pts
(8
5.7
%)
in
the
OIT
gro
up
pre
se
nte
d Sx
w
ith
at
leas
t 1
dos
e.
Thes
e Sx
nev
-er
oc
curr
ed
after
the
pts
re
ache
d 5
0
mL
of
CM.
All
Sx
wer
e m
ild a
nd lo
cal
AEs
, m
ainl
y in
th
e fo
rm
of i
mm
edia
te
rash
ar
ound
th
e m
onth
, in
cre
as
ed
prur
itus,
or
si
ngle
whe
als.
In
th
e CG
, 3
of
1
2
pts
(25
.0%
) ha
d m
ild
AEs
, p
ro
ba
bly
ca
used
by
ac
cide
ntal
ex-
posu
re to
CM
, an
d ea
sily
re-
cove
red
with
-ou
t tre
atm
ent
or
after
th
e us
e of
or
al
AH
.
Tabl
e S1
Con
tinue
d
E-29EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Longo, 2008, Italy
60
chi
ldre
n ra
ndom
ized
in
OIT
gro
up
(n=
30
, mea
n ag
e 7
.9 y
rs)
and
milk
–f
ree
diet
(n
=3
0, m
ean
age
8.1
yrs
); H
x of
sev
ere
CM-i
nduc
ed
SRs
(+),
SPT
(+),
sIgE
(+),
DB
PCFC
(+).
RCT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
cow
‘ s m
ilkO
IT
had
2
phas
es:
the
1st
(r
ush
phas
e) t
ook
plac
e in
the
hos
pita
l for
1
0 d
ays.
1st
day
: 6 d
oses
of
dilu
t-ed
milk
at
1-h
our
inte
rval
s; s
econ
d,
thir
d, a
nd fo
urth
day
: 4 d
oses
of
di-
lute
d m
ilk a
t 2
-hou
r in
terv
als;
and
th
en 3
dai
ly d
oses
at
2-h
our
inte
r-va
ls, i
ncre
asin
g th
e co
ncen
trat
ion
of
the
solu
tion
each
day
to re
ach
who
le
milk
(up
to
20
ml,
cum
ulat
ive
dose
4
9 m
l pur
e CM
in t
he 1
0th
day
). A
ll ch
ildre
n w
ere
give
n A
H d
aily
(ox
-at
omid
e, 1
mg/
kg p
er d
ay).
Afte
r di
scha
rgin
g fr
om h
ospi
tal
child
ren
follo
wed
a s
low
incr
easi
ng p
hase
(in-
crea
sing
by
1 m
l eve
ry s
econ
d da
y)
pers
onal
ized
for
each
pt,
on t
he b
a-si
s of
the
fre
quen
cy a
nd s
ever
ity o
f A
Es a
nd c
onfid
ence
of p
aren
ts; w
hen
hom
e do
sing
rea
ched
15
0 m
l of
w
hole
milk
in a
sin
gle
dose
, the
pts
w
ere
aske
d to
eat
oth
er d
airy
pro
d-uc
ts. A
H c
ontin
ued
at h
ome
as w
ell
until
the
y re
ache
d 1
50
ml
of m
ilk,
and
then
red
uced
with
in 4
wks
. OIT
w
as c
onsi
dere
d to
hav
e fa
iled
if th
e ch
ild d
id n
ot r
each
at
leas
t 5
ml o
f un
dilu
ted
milk
in a
sin
gle
dose
afte
r 1
yr
or if
pts
wer
e st
oppe
d fo
r A
Es.
Afte
r 1
yr
of
O
IT,
in t
he A
G:
11
(3
6%
) pt
s ac
hiev
ed
a da
ily i
ntak
e of
CM
> 1
50
mL,
m
any
of t
hem
w
ith t
he a
ddi-
tion
of d
iffer
ent
dair
y pr
od-
ucts
, en
ough
to
pe
rmit
an
un
rest
rict
ed
diet
; 16
(54
%)
wer
e ab
le
to
take
a
limite
d am
ount
of
CM
(5 t
o 1
50
mL)
, an
d 3
(1
0%
) w
ere
not
able
to
con
tinue
in
the
stud
y be
-ca
use
of
AEs
. In
CG
, no
sub
-je
ct a
fter
a yr
re
ache
d sp
on-
tane
ous
tol-
eran
ce
to
CM
(pos
itive
D
BP-
CFC)
. [E
ffica
cy
of O
IT,
AG
vs
CG: P
< .0
01
]
In
th
e ru
sh
phas
e:
i.m. E
4 t
imes
in 4
ch
ildre
n, n
ebul
ized
E
in
18
ch
ildre
n an
d m
ore
than
on
ce i
n 7
pts
for
re
curr
ing
resp
ira-
tory
Sx.
Slow
(h
ome)
do
s-in
g: 2
pts
req
uire
d tr
eatm
ent
in
the
emer
genc
y de
part
-m
ent
(ora
l CS,
AH
, an
d i.m
. E (1
cas
e).
In
AG
, al
mos
t al
l pt
s pr
e-se
nted
with
1
or m
ore
alle
r-gi
c Sx
, mai
nly
cu
tan
eo
us
(U
and
an-
gioe
dem
a) o
r ab
dom
inal
. In
CG
, 6
(2
0%
) pt
s ha
d m
ild
AEs
(acc
iden
-ta
l exp
osur
e).
Tabl
e S1
Con
tinue
d
E-30 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Martorell, 2011, Spain
60
chi
ldre
n (a
ged
24
-36
m
o) ra
nd-
omiz
ed in
to:
OIT
gro
up
(n =
30
) or
CG (n
=3
0)/
H
x (+
), SP
T (+
), sI
gE (+
), D
BPC
FC (+
).
par-
alle
l- gr
oup,
m
ul-
ti-ce
n-tr
e R
CT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
cow
‘ s m
ilkD
ay 1
in
hosp
ital:
dose
s ho
urly
; m
ilk
dose
s (m
l):
A)
dilu
tion
1/1
00
: 1
,2,3
,4,8
; B) D
ilutio
n 1
/10
: 1.6
ml.
Day
2 in
hos
pita
l: m
ilk d
oses
(m
l): A
) di
lutio
n 1
/10
, do
ses
hour
ly:
1.6
, 3
.2; 6
;12
ml a
nd B
) pu
re m
ilk: 2
.5
ml;
Dos
e m
aint
aine
d at
hom
e, w
ith e
le-
vatio
n on
ce a
wee
k in
hos
pita
l (to
tal
16
wks
) fro
m 4
up
to 2
00
ml o
f pur
e CM
. A
t th
e en
d of
the
stu
dy,
OD
was
of-
fere
d to
the
pts
in t
he A
G w
ho h
ad
not a
chie
ved
tole
ranc
e
Afte
r 1
-yr
fol-
low
-up
peri
od,
90
% o
f pt
s in
A
G
wer
e de
-se
nsiti
zed.
1
pt
ab
ando
ned
the
stud
y as
a
resu
lt of
mov
-in
g ho
use
be-
fore
re
achi
ng
the
max
imum
do
se.
Ano
ther
pt
ab
ando
ned
the
stud
y du
e to
po
or
tol-
eran
ce
of
the
OD
pr
otoc
ol
(U,
RC,
co
ugh
and
whe
ez-
ing
on
reac
h-in
g th
e 2
.5 m
l do
se),
whi
le
part
ial
OD
w
as
achi
eved
in
an
othe
r pt
(3
5m
L of
milk
) In
the
CG
, af
-te
r 1
2 m
o of
fo
llow
-up,
D
B-
PCFC
was
per
-fo
rmed
in
2
3
/30
pt
s an
d pr
oved
ne
ga-
tive
in 3
(23
%,
natu
ral
tole
r-an
ce)
N
one
24
pt
s in
A
G
(80
%)
[14
m
od
era
te
(47
%)
and
10
m
ild
(33
%)
re-
actio
n].
The
mos
t co
m-
mon
man
ifes-
tatio
ns
wer
e U
-ang
ioed
e-m
a,
follo
wed
by
cou
gh.
Tabl
e S1
Con
tinue
d
E-31EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Meglio, 2013, Italy
20
chi
ldre
n (m
edia
n ag
e 8
.4 y
s)
alle
rgy
rand
-om
ized
into
: O
IT g
roup
(n
=1
0) o
r co
ntro
l gro
up
(n =
10
). /
Hx
(+),
SPT
(+),
sIgE
(+
), D
BPC
FC
(+) u
nles
s co
nvin
cing
hi
stor
y of
lif
e-tr
eat-
enin
g A
Es
after
min
imal
am
ount
of H
E
open
R
CTO
IT v
s ro
utin
e ca
re
(foo
d av
oid-
ance
)
egg
Initi
al d
ay e
scal
atio
n ph
ase:
Sta
rted
fr
om 1
dro
p (m
ixed
raw
egg
whi
te
and
yolk
) di
lute
d 1
:10
0 w
ith w
a-te
r, c
orre
spon
ding
to
0.2
7 m
g of
H
E pr
otei
ns.
This
dos
e w
as a
dmin
-is
tere
d in
hos
pita
l; th
e fo
llow
ing
by
pare
nts
at h
ome.
Bui
ld-u
p ph
ase:
Th
e H
E do
ses
wer
e do
uble
d ev
ery
8
days
unt
il da
y 8
0. S
ubse
quen
tly, t
he
HE
dose
s w
ere
doub
led
ever
y 1
6
days
to
achi
eve
a to
tal d
aily
int
ake
of 2
5 m
l in
6 m
o. C
hild
ren
unde
r-w
ent 0
.25
mg/
kg/d
ay c
etir
izin
e pe
r os
dur
ing
the
stud
y.
8/1
0
child
ren
(80
%)
in
the
AG
ac
hiev
ed
the
daily
int
ake
of 2
5 m
l ov
er
a 6
-mon
th
pe-
riod
(p
< 0
.01
, in
co
mpa
riso
n to
CG
). 1
chi
ld
(10
%)
coul
d to
lera
te
up
to
2 m
l/da
y w
hile
an
othe
r ch
ild
(10
%)
faile
d th
e de
sens
itisa
-tio
n. 2
chi
ldre
n (2
0%
) in
the
CG
coul
d to
lera
te
HE
after
6 m
o si
nce
the
enro
ll-m
ent
spon
tane
-ou
sly
3 o
f 1
0 p
ts i
n A
G
reac
hed
the
full
dose
w
ithou
t an
y A
Es.
6/1
0
child
ren
dur-
ing
the
OIT
p
res
en
ted
som
e m
ild S
x,
whi
ch
star
ted
shor
tly
after
in
gest
ing
HE,
pe
rsis
ted
for
<2
h a
nd r
e-so
lved
sp
on-
tan
eo
us
ly.
1/1
0
child
ha
d U
and
pru
-ri
tus
arou
nd
3
ml
of
raw
H
E an
d th
e tr
eatm
ent
was
st
oppe
d.
Morisset, 2007, France
CMA
: 57
pt
s (m
ean
age
2.2
± 1
yr
s, ra
nge
13
mo
- 6
.5
yrs)
rand
-om
ized
to A
G
(n=
27
) and
CG
(n=
30
) fo
r 6
mo;
HE
alle
rgy:
AG
(n
=4
9, m
ean
age
3.5
yrs
); CG
(n=
35
, m
ean
age
3.6
yrs
) ) /
H
x (+
), SP
T (+
), sI
gE (+
), D
BPC
FC (+
)
RCT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
cow
´s m
ilk
and
hen´
s eg
g
OD
pro
toco
l usi
ng w
hole
pas
teur
ized
m
ilk: 1
st w
k fr
om 1
ml (
day
1) t
o 2
0
ml (
day
5-7
); 2
nd w
k 5
0 m
l/da
y; 3
rd
wk
10
0 m
l/da
y; 4
th w
k 1
00
ml/
day
and
intr
oduc
tion
of c
ream
des
sert
s,
yogh
urts
or
crea
m c
hees
e; 5
th a
nd
6th
wk
25
0 m
l/da
y an
d da
iry
prod
-uc
ts; 7
th w
k an
d th
erea
fter:
rou
tine
amou
nts,
not
qua
ntifi
ed.
OD
pro
toco
l w
ith h
ard-
boile
d eg
gs:
1st
wk
1 g
of
egg
yolk
onc
e a
day,
ev
ery
day;
2nd
wk
1 g
of
yolk
and
1
g E
W o
nce
a da
y, e
very
day
;3rd
w
k 2
g o
f yol
k an
d 2
g o
f EW
onc
e a
day,
eve
ry o
ther
day
; 4th
wk
4 g
of
yolk
and
4 g
of E
W o
nce
a da
y, e
very
ot
her
day;
2nd
mon
th: i
ntro
duct
ion
of b
iscu
its a
nd c
rack
ers,
etc
; 3
rd
mon
th:
intr
oduc
tion
of fl
ans,
cre
am
dess
erts
CM:
A
SBPC
FC
(up
to 2
00
ml
of
milk
) w
as
posi
tive
in
11
.1%
(3
/27
) of
thos
e fo
llow
-in
g O
D v
s 4
0%
(1
2/3
2)
in C
G
(p<
0.0
25
) af
-te
r 6
mo.
H
E:
A
SBPC
FC
(up
to 7
mg
of
raw
egg
whi
te)
was
po
sitiv
e in
3
0.6
%
(15
/49
) of
th
ose
follo
win
g O
D
vs
48
.6%
(1
7/3
5)
in C
G
(p<
0.1
) aft
er
6 m
o.
Unc
lear
repo
rtin
g
Tabl
e S1
Con
tinue
d
E-32 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Pajno, 2010, Italy
30
chi
ldre
n (a
ged
4 -
10
yr
s) ra
nd-
omiz
ed in
: AG
(m
ilk, n
=1
5);
and
CG (s
oy,
n=1
5) /
Hx
(+),
SPT
(+),
sIgE
(+),
DB
PCFC
(+)
Ran
d-om
i-se
d si
n-gl
e-bl
ind
con-
trol
-le
d st
udy
OIT
vs
plac
ebo
cow
´s m
ilkFr
esh
CM o
r soy
form
ula
was
adm
inis
-te
red
at th
e cl
inic
at w
eekl
y in
terv
als
at in
crea
sing
dos
es. T
he in
itial
dos
e st
arte
d fr
om 1
dro
p of
who
le m
ilk
dilu
ted
1:2
5. T
he d
ose
was
dou
bled
ev
ery
wee
k at
the
clin
ic u
ntil
wee
k 1
8 to
ach
ieve
an
inta
ke o
f 20
0 m
l.
10
pts
in
the
AG
ac
hiev
ed
full
tole
ranc
e to
CM
(2
00
m
l) an
d in
1
pt
pa
rtia
l to
lera
nce
(10
0
mL)
[10
/13
tol-
eran
ce o
n pr
o-to
col,
10
/15
on
int
entio
n to
tr
eat]
In
2
pt
s SR
s (r
e-qu
irir
ing
epin
e-ph
ine)
oc
curr
ed
and
then
st
oppe
d O
IT.
7 p
ts h
ad m
ild
AEs
(a
bdom
-in
al
pain
, th
roat
pr
u-ri
tis,
gritt
y ey
es).
They
w
ere
tran
-si
ent
(and
on
ly in
1 c
ase
AH
wer
e gi
v-en
)
Patriarca, 1998, Italy
OIT
gro
up:
n=1
4; 4
-14
yr
s ol
d,
med
ian
age
5.5
yrs
; 6
/14
mal
e (4
3%
).1 fe
-m
ale
ente
red
3 ti
mes
whe
n de
sens
itize
d to
milk
, egg
, fis
h. H
ence
2
4 p
ts in
tria
l fr
om 2
2 in
di-
vidu
als.
Con
-tr
ols:
(n=
10
) ag
ed 5
-13
yr
s (m
edia
n 7
.5yr
s);
6/1
0 m
ale
(60
%) /
Hx
(+),
SPT
(+),
sIgE
(+),
DB
PCFC
(+)
(unl
ess
one
who
had
Hx
posi
tive
for
life
thre
aten
-in
g re
actio
n)
RCT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
CM [O
IT: n
=
6 (4
3%
); CG
: n=
5
(50
%)]
; Eg
g [O
IT n
=
5 (3
6%
); CG
: n=
4
(40
%)]
; Fi
sh [O
IT: n
=
2 (1
4%
); CG
: n=
1
(10
%)]
; A
pple
[O
IT: n
= 1
(7
%);
CG:
n=0
(0%
)]
Initi
al d
ay e
scal
atio
n ph
ase:
Pu
re M
ilk 1
0 d
rops
10
ml;
days
1-1
2,
4 d
rops
incr
ease
d to
12
/day
;Pu
re s
hake
n Eg
g 1
0 d
rops
egg
in 1
00
m
l wat
er; d
ays
1-2
0 4
dro
ps t
o 3
6
drop
s x
3;
Fish
(bo
iled
cod)
10
ml
6%
fish
ex-
trac
t in
90
ml w
ater
; day
s 1
to 2
4 4
dr
ops
to 1
08
dro
ps;
App
le (
pure
app
le m
ix)
1 m
l ap
ple
mix
ed in
9 m
l wat
er; d
ays
1 to
34
1
drop
x 2
to 6
dro
ps x
4;
Bui
ld-u
p ph
ase:
Pure
Milk
13
to
10
4 d
rops
1 d
rop
milk
to 3
0 m
l x4
;Pu
re s
hake
n Eg
g 2
1 t
o 9
0 1
dro
p to
3
0 m
l x 3
;Fi
sh (b
oile
d co
d) 2
5 to
12
0 1
5 d
rops
6
% e
xtra
ct to
20
0 g
boi
led
fish/
day;
App
le (
pure
app
le m
ix)
35
to
10
9 1
dr
op a
pple
mix
to 1
app
le a
day
;M
aint
enan
ce p
hase
(4 m
o):
Pure
Milk
10
0 m
l 2
-3x/
wee
k; P
ure
shak
en E
gg 1
egg
2-3
x/w
eek;
Fis
h (b
oile
d co
d) 2
00
g b
oile
d/w
eek;
Ap-
ple
(pur
e ap
ple
mix
) 1-
2x/
wee
k.
In
OIT
gr
oup,
1
2/1
4
(86
%)
succ
ess
full
y ab
le t
o ea
t an
y fo
ods
with
out
prob
lem
s in
3
-6
yr-
long
fo
llow
-up;
2
fa
ilure
s du
e to
at
tend
ance
.In
CG
all
DB
PCFC
at
6 m
o w
ere
posi
tive,
as
w
ell a
s SP
T an
d sI
gE
at
6
mo
(OD
, AG
vs
CG,
P<0
.00
01
)
Non
eIn
AG
: 6/1
4 U
, 2
as
thm
a,
1
angi
oede
ma,
2
ab
dom
inal
pa
in,
4 n
one;
al
l A
Es
wer
e m
ild a
nd e
as-
ily
cont
rolle
d by
AH
Tabl
e S1
Con
tinue
d
E-33EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Salmivesi, 2012, Finland
28
chi
ldre
n (a
ged
6-1
4
yrs)
rand
-om
ized
into
2
gro
ups:
AG
(n
=1
8) a
nd
CG (n
=1
0) /
H
x (+
), SP
T (+
), sI
gE (+
), D
BPC
FC (+
)
DB
P-CR
TO
IT v
s pl
aceb
o co
w‘ s
milk
Bui
ld u
p ph
ase
The
1st
dos
e (0
.06
mg)
an
d 8
late
r do
ses
wer
e gi
ven
in t
he
outp
t cl
inic
. The
am
ount
of m
ilk p
ro-
tein
(pas
teur
ized
2.5
% fr
esh
milk
) in-
crea
sed
daily
dou
bled
eve
ry w
k, fr
om
0.0
6 t
o 6
40
0 m
g. T
he fi
nal d
ose
of
64
00
mg
was
giv
en a
t ho
me
on d
ay
16
2, a
nd c
ontr
ol v
isit
was
hel
d w
ithin
2
wks
, all
othe
r do
se in
crea
ses
wer
e pe
rfor
med
at
hom
e ac
cord
ing
to a
pr
ospe
ctiv
e, d
aily
sch
edul
e. M
anta
in-
ance
pha
se T
hen
the
AG
pts
who
had
co
mpl
eted
the
OIT
pro
toco
l tot
ally
or
part
ially
, con
tinue
d da
ily C
M u
se, e
i-th
er 2
00
mL
or C
M p
rodu
cts
(64
00
m
g m
ilk p
rote
in)
or a
low
er a
mou
nt
reac
hed
duri
ng O
IT.
All
10
chi
ldre
n in
the
CG
suc
cess
fully
com
plet
ed a
n op
en-la
ble
OIT
by
an id
entic
al p
roto
-co
l pla
cebo
(oat
milk
, ric
e m
ilk o
r soy
m
ilk, d
epen
ding
on
the
alle
rgy
stat
us
of th
e ch
ild)
24
(8
6%
) pt
s c
om
ple
ted
the
prot
o-co
l: 1
6/1
8
in
AG
an
d 8
/10
in
CG
. A
fter
OIT
: 1
4
chil-
dren
to
lera
ted
64
00
mg,
and
ot
her
two
96
0
and
19
20
mg
Bef
ore
OIT
non
e,
after
ope
n la
bel
OIT
all
child
ren
in t
he p
revi
ous
plac
ebo
grou
p to
lera
ted
20
0
ml m
ilk.
D
urin
g th
e O
D
pe-
riod
, in
th
e A
G:
whe
ezin
g in
5 p
ts
(19
.2%
) bu
t no
em
erge
ncy
room
s w
ere
need
ed.
Follo
w-u
p 3
.0-3
.5
yrs
late
r: o
ne c
hild
ha
d st
oppe
d us
-in
g di
ary
prod
ucts
be
caus
e of
sev
ere
ecze
ma
and
seve
re
A;
1
anap
hyla
ctic
re
actio
n to
ok p
lace
w
hen
CM
avoi
d-an
ce w
as re
stor
ed.
AG
: su
bjec
tive
ab
do
min
al
and
oral
Sx
; CG
: su
bjec
-tiv
e ab
dom
-in
al
and
oral
Sx
Skripak, 2008, USA
20
pts
(age
d 6
to 2
1 y
rs)
rand
omiz
ed
into
: AG
(n
=1
3; m
ale
8, m
ean
age
and
SD 9
.3
± 3
.3 fr
om
the
pedi
at-
ric
clin
ics)
an
d pl
aceb
o gr
oup
(n=
7,
mal
e 4
, mea
n ag
e an
d SD
1
0.2
± 3
.3)
/ H
x (+
), SP
T (+
), sI
gE (+
), D
BPC
FC (+
)
DB
P-CR
TO
IT v
s pl
aceb
o co
w‘ s
milk
On
the
first
day
of
trea
tmen
t, a
dose
es
cala
tion
was
initi
ated
in th
e ho
spi-
tal w
ith 0
.4 m
g of
milk
pro
tein
(dr
y no
n-fa
t po
wde
red
milk
); do
ublin
g do
ses
wer
e gi
ven
ever
y 3
0 m
inut
es
to a
max
imum
of 5
0 m
g (c
umul
ativ
e do
se, 9
8.7
mg)
; pts
had
to
tole
rate
a
min
imum
dos
e of
12
mg
(cum
ula-
tive
dose
, 23
.7 m
g) t
o pr
ocee
d w
ith
hom
e do
sing
. B
uild
up
phas
e H
ome
dose
was
initi
-at
ed a
t th
e hi
ghes
t do
se t
oler
ated
on
the
dos
e es
cala
tion
day.
Afte
r 7
to
14
day
s on
a g
iven
dos
e, p
ts
retu
rned
to th
e ho
spita
l to
rece
ive
a do
se in
crea
se.
Mai
nten
ance
pha
se O
nce
a do
se o
f 5
g (e
quiv
alen
t to
15
ml o
f milk
) was
ac
hiev
ed,
they
co
ntin
ued
on
that
do
se d
aily
for
13
wks
, aft
er w
hich
th
ey u
nder
wen
t DB
PCFC
.
The
med
ian
milk
th
resh
old
dose
in
bot
h gr
oups
w
as 4
0 m
g at
th
e ba
selin
e D
BPC
FC,
after
O
IT i
n th
e A
G,
12
/13
pat
ient
re
ache
d O
D.
Tthe
m
edia
n c
um
ula
tiv
e do
se
indu
c-in
g a
reac
tion
was
51
40
mg
(ran
ge
25
40
-8
14
0);
all
pts
in
the
PG
re-
acte
d at
40
mg
(OD
, AG
vs
CG:
P=0
.00
03
)
Am
ong
24
37
act
ive
OIT
dos
es v
s 1
19
3
plac
ebo
dose
s,
ther
e w
ere
11
07
(4
5.4
%)
vs
13
4
(11
.2%
) to
tal A
Es;
SRs
(GI,
low
er r
es-
pira
tory
tra
ct,
and
skin
Sx)
wer
e ra
re,
occu
rrin
g w
ith
a m
edia
n fr
eque
n-cy
of
1%
of
activ
e do
ses
vs.
none
in
the
plac
ebo
grou
p (P
=0
.01
) Sk
in A
Es
0.9
%
vs.
0.1
%
(p=
0.1
) Re
spira
to-
ry 8
.1%
vs.
2.3
%
(p=
0.3
)
LRs
(ora
l pr
u-ri
tis,
abdo
mi-
nal p
ain)
with
a
med
ian
freq
uenc
y of
1
6%
and
2%
of
act
ive
dos-
es,
resp
ec-
tivel
y (P
=
0.0
06
an
d 0
.02
, res
pec-
tivel
y)
Tabl
e S1
Con
tinue
d
E-34 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Staden, 2007, Germany
45
chi
ldre
n (2
9 m
ale,
m
edia
n ag
e 2
.5 y
rs,
rang
e 0
.6-
12
.9 y
rs)
rand
omiz
ed
in 2
gro
ups:
O
IT g
roup
(C
M n
=1
4,
HE
n=1
1)
and
CG (C
M:
n=1
0; H
E:
n=1
0).
/ H
x (+
), SP
T (+
), sI
gE (+
), D
B-
PCFC
(+) [
47
re
crui
ted,
45
re
port
ed, 2
lo
st to
follo
w
up o
r fa
iled
to s
tart
]
RCT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
cow
‘ s m
ilk
and
hen´
s eg
g
OIT
was
car
ried
out
at h
ome.
In
duct
ion
phas
e: C
M s
tart
ing
dose
: 0
.02
m
g CM
pr
otei
n fr
om
3.5
%
fres
h pa
steu
rize
d CM
; HE
- st
artin
g do
se: 0
.00
6 m
g ly
ophi
lized
HE
pro-
tein
. B
uild
-up
phas
e: D
oses
wer
e in
crea
sed
acco
rdin
g to
the
indi
vidu
al to
lera
nce
to a
max
imum
dos
e of
82
50
mg
CM
prot
ein
(25
0 m
l CM
) or
28
00
mg
HE
prot
ein
(aro
und
½ H
E).
Med
ian
peri
od
to
reac
h th
e m
anta
inan
ce
dose
7 m
o.
Mai
nten
ance
pha
se: a
min
imum
dai
ly
mai
nten
ance
dos
e of
33
00
mg
CM
prot
ein
(10
0 m
l CM
) an
d 1
60
0 m
g H
E pr
otei
n (a
roun
d ¼
HE)
plu
s de
-lib
erat
e in
take
. Med
ian
mai
nten
ance
ph
ase
9 m
o (r
ange
7-1
5 m
o).
Afte
r O
D, t
he A
G r
ecei
ved
an e
limin
a-tio
n di
et fo
r 2
mo
prio
r to
follo
w-u
p D
BPC
FC t
o ev
alua
te O
T. O
T fo
r al
l ch
ildre
n w
as fi
nally
eva
luat
ed a
fter
a m
edia
n of
21
mo
(ran
ge 1
2-4
7)
cons
ider
ing
AG
and
PG
.
A
t fo
llow
-up
DB
PCFC
9
of
2
5 p
ts (
36
%)
show
ed p
erm
a-ne
nt
tole
ranc
e in
th
e A
G;
3
of
25
(1
2%
) w
ere
tole
rant
w
ith
regu
lar
inta
ke
and
4
of
25
(1
6%
) w
ere
part
ial
res
po
nd
ers
; in
the
CG
, 7 o
f 2
0 p
ts (
35
%)
wer
e to
lera
nt.
Ove
rall,
16
/25
(6
4%
) w
ere
tole
rant
(to
tal-
ly o
r par
tially
in
AG
, an
d 7
/20
(3
5%
) in
CG
(P
=0
.05
).
In
the
AG
, in
4 p
ts:
gene
raliz
ed
U,
bron
chia
l ob
stru
c-tio
n, o
r an
gioe
de-
ma
(tre
ated
w
ith
AH
and
Cs)
; in
the
CG
1 c
hild
had
se-
vere
A
Es
(vom
it-in
g, p
alen
ess,
cir
-cu
lato
ry
diso
rder
) aft
er
acci
dent
al
expo
sure
; 2
pt
s du
ring
fo
llow
-up
DB
PCFC
had
bro
n-ch
ial
obst
ruct
ion,
ge
nera
lized
U,
and
circ
ulat
ory
dis-
orde
rs
and
wer
e eq
uipp
ed
with
an
E
self-
adm
inis
tra-
tion-
pen.
In
AG
, 2
1/2
pt
s (8
4%
) m
ild S
x
Tabl
e S1
Con
tinue
d
E-35EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Tang, 2015, Australia
62
pts
(age
d 1
–10
yrs
, av
erag
e 6
yr
s) o
f bot
h se
xes;
[pt a
l-lo
catio
n: A
G
(n =
31
); pl
a-ce
bo (n
=3
1)]
/
Hx
(+),
SPT
(≥ 8
mm
) to
pea
nuts
, an
d sI
gE to
pe
anut
(≥ 1
5
kU/L
).
DB
P-CR
T(O
IT +
pr
obi-
otic
) vs
plac
ebo
pean
utTh
e A
G r
ecei
ved
Lact
obac
illus
rha
m-
nosu
s CG
MCC
1.3
72
4 (
NCC
40
07
; pr
ovid
ed b
y N
estle
Hea
lth S
cien
ce,
Kon
olfin
gen,
Sw
itzer
land
) at
a fi
xed
dose
of
2 *
10
10
col
ony-
form
ing
units
(f
reez
e-dr
ied
pow
der)
on
ce
daily
toge
ther
with
pea
nut O
IT (p
ea-
nut fl
our,
50
% p
eanu
t pro
tein
) onc
e da
ily a
ccor
ding
for
18
mo.
The
CG
re
ceiv
ed p
lace
bo (m
alto
dext
rin)
and
pl
aceb
o (m
alto
dext
rin,
bro
wn
food
co
lori
ng, a
nd p
eanu
t es
senc
e) o
nce
daily
. Act
ive
and
plac
ebo
OIT
pro
d-uc
ts w
ere
sim
ilar
in ta
ste,
col
or, a
nd
smel
l.Th
e pe
anut
OIT
pro
toco
l co
mpr
ised
a1
-day
ru
sh
indu
ctio
n ph
ase
(8
dose
s: 0
.1 m
g -
12
mg
of p
eanu
t pr
otei
ns,
cum
ulat
ive
final
dos
e 2
4
mg
of p
eanu
t pr
otei
ns),
a bu
ild-u
p ph
ase
with
upd
osin
g ev
ery
2 w
ks
from
25
mg
up to
mai
nten
ance
dos
e of
2 g
of p
eanu
t pro
tein
(8 m
o), a
nd
a m
aint
enan
ce p
hase
(10
mo)
; tot
al
OIT
was
18
mo.
Whe
re t
he b
uild
-up
phas
e w
as l
onge
r th
an 8
mo
(be-
caus
e of
AEs
) bu
t le
ss t
han
12
mo,
th
e m
aint
enan
ce p
hase
was
adj
ust-
ed t
o pr
eser
ve a
tot
al o
f 1
8 m
o of
O
IT.
For
pts
taki
ng m
ore
than
12
m
o to
rea
ch m
aint
enan
ce, t
he t
otal
du
ratio
n of
OIT
was
ext
ende
d to
en-
sure
a m
inim
um o
f 6
mo
of m
aint
e-na
nce
dosi
ng.
89
.7%
of p
ts re
-ce
ivin
g PP
OIT
an
d 7
.1%
re
-ce
ivin
g pl
ace-
bo
wer
e de
-se
nsiti
zed
(P <
.0
01
).
PPO
IT w
as e
ffec-
tive
in in
duci
ng
poss
ible
su
s-ta
ined
un
re-
spo
nsiv
enes
s in
8
2.1
%
re-
ceiv
ing
PPO
IT
and
3.6
%
re-
ceiv
ing
plac
ebo
(P<
.00
1).
The
rela
tive
RR
of
ac
hiev
ing
pos-
sibl
e su
stai
ned
un
re
sp
on
-si
vene
ss
with
PP
OIT
was
23
(9
5%
CI,
3.3
3-
15
8.8
), pr
o-vi
ding
an
NN
T of
1.2
7 (
95
%
CI,
1.0
6-1
.59
) [P
< .0
01
].
A
t le
ast
1
seve
re
AE
was
rep
orte
d in
4
5.2
% o
f pts
in A
G
and
32
.3%
in
CG
(P=
.3
). Th
e to
tal
num
ber
of s
ever
e A
Es w
as g
reat
er in
A
G t
han
in C
G (
34
an
d 1
5,
resp
ec-
tivel
y),
but
this
re
flect
ed 1
chi
ld in
th
e A
G w
ho h
ad 1
3
seve
re
AEs
. Th
e nu
mbe
r of
sev
ere
AEs
per
pt
did
not
diffe
r by
gro
up (
P =
.9
). A
Es d
urin
g ru
sh i
nduc
tion
and
build
-up
wer
e si
m-
ilarly
di
stri
bute
d be
twee
n gr
oups
. H
owev
er,
AEs
dur
-in
g th
e m
aint
e-na
nce
phas
e w
ere
mor
e co
mm
on
in
AG
th
an
CG.
10
se
vere
SR
s in
7
pt
s:
3
in
the
AG
an
d 4
in C
G. A
ll bu
t 1
oc
curr
ed
dur-
ing
the
Aus
tral
ian
polle
n se
ason
(A
u-gu
st-F
ebru
ary)
.
AG
- pt
s re
port
-ed
a g
reat
er
num
ber
of
AEs
, m
ostly
w
ith
mai
nte-
nanc
e ho
me
dosi
ng
Tabl
e S1
Con
tinue
d
E-36 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Varshney, 2011, USA
28
pts
(age
d 2
-10
yrs
) ra
ndom
ized
in
: AG
[n=
19
, m
edia
n ag
e 8
4 m
o, ra
nge
(38
-12
6)]
an
d CG
[n=
9,
age
(mo)
, 69
(2
8-1
14
)] /
H
x (+
), SP
T (+
), sI
gE (+
), D
BPC
FC (+
)
DB
P-CR
CTO
IT v
s pl
aceb
o pe
anut
Initi
al d
ay e
scal
atio
n ph
ase:
in c
linic
al
sett
ing:
0.1
mg
pean
ut p
rote
in (
as
flour
) or p
lace
bo; d
ose
doub
led
ever
y 3
0 m
inut
es u
ntil
6 m
g or
Sx.
B
uild
-up
phas
e: i
n cl
inic
al s
ettin
g 1
st
day
dose
fro
m e
scal
atio
n ph
ase
day
befo
re;
ever
y 2
wks
dos
e in
crea
sed
by 5
0-1
00
% u
ntil
75
mg/
day
tol-
erat
ed,
then
25
-33
% u
ntil
mai
nte-
nanc
e do
se o
f 4
g ac
hiev
ed w
ithin
4
4 w
ks.
At
hom
e th
e do
sing
was
re
sum
ed if
chi
ldre
n m
isse
d le
ss t
han
3 d
aily
dos
es, i
f fr
om 3
to
5 d
oses
w
ere
mis
sing
chi
ldre
n re
turn
ed fo
r an
obse
rved
dos
e.M
aint
enan
ce p
hase
: 4 g
/day
, for
1 m
o th
en re
turn
ed fo
r DB
PCFC
at 4
8 w
ks.
16
/19
in
A
G
reac
hed
mai
n-te
nanc
e do
se,
9/9
in
CG
. A
t D
BPC
FC
all
16
/16
in
A
G
inge
sted
5
00
0
mg
(app
roxi
-m
atel
y 2
0 p
ea-
nuts
); w
hile
pla
-ce
bo p
ts (
n=9
) in
gest
ed a
me-
dian
cum
ulat
ive
dose
of 2
80
mg
(ran
ge, 0
-19
00
m
g) [p
<0
.00
1].
Pts
requ
irin
g E:
at
th
e in
itial
day
es-
cala
tion,
2 i
n A
G;
at
hom
e do
sing
1
pt
in C
G (
after
pl
aceb
o);
at D
BP-
CFC
0/1
6 a
nd 3
/9
need
ed E
in A
G a
nd
CG, r
espe
ctiv
ely.
At
the
initi
al
day
esca
la-
tion
9
pts
(47
%)
in A
G
need
ed
AH
. D
urin
g bu
ild
up
phas
e1
pts
in
AG
w
ithdr
ew
af-
ter
mild
GI S
x at
the
1st
es-
cala
tion
dose
; aft
er t
he D
B-
PCFC
1 p
t in
A
G
had
mild
U
+R
, tr
eate
d w
ith A
H.
CCT
(N=
6)
García-Ara, 2013, Spain
55
pts
alle
r-gi
c to
CM
[36
bo
ys (6
3%
); m
edia
n ag
e,
7 y
rs; r
ange
, 4
-14
yrs
] co
nfirm
ed
by O
FC w
ere
assi
gned
to
OIT
(n=
36
) or
elim
inat
ion
diet
if th
ey
refu
sed
to
unde
rgo
OIT
aft
er th
e O
FC
(n =
19
)
CCT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
cow
‘ s m
ilkTh
e in
itial
dos
e fo
r O
IT w
as t
he p
re-
viou
s do
se t
hat
elic
ited
Sx i
n th
e O
FC. T
he la
tter
sta
rted
at
a do
se o
f 0
.00
5 m
L an
d th
en d
oses
wer
e do
u-bl
ed u
ntil
1 m
or
an o
bjec
tive
clin
-ic
al r
eact
ivity
was
ach
ieve
d. U
ntil
a do
se o
f 1
mL
was
ach
ieve
d, d
oses
w
ere
incr
ease
d at
the
hos
pita
l se
t-tin
g in
a d
aily
bas
is. F
rom
the
re o
n,
dose
s w
ere
incr
ease
d w
eekl
y at
the
ho
spita
l, an
d pt
s m
aint
aine
d th
is
dose
tw
ice
daily
at
hom
e. A
chie
v-in
g an
inta
ke o
f 2
00
mL
of m
ilk (
6
g of
pro
tein
s) t
wic
e a
day,
whi
ch is
th
e us
ual a
mou
nt fo
r pts
of t
hat a
ge,
was
con
side
red
succ
essf
ul d
esen
si-
tizat
ion.
In
the
mai
nten
ance
pha
se,
follo
w-u
p vi
sits
wer
e sc
hedu
led
at 1
m
onth
, 6 m
o, a
nd 1
yr a
fter fi
nish
ing
indu
ctio
n ph
ase
33
ou
t of
3
6
pts
in A
G w
ere
de
sen
siti
zed
(20
0
ml).
3
w
ithdr
awal
s in
th
e O
IT g
roup
: 1
pt
be
caus
e of
ps
ycho
logi
-ca
l st
ress
, an
d 2
pts
bec
ause
of
rep
eate
d di
-ge
stiv
e Sx
. De-
sen
siti
zati
on
was
ac
hiev
ed
in a
med
ian
of
3
mo
(ran
ge,
1-1
2
mo)
. In
th
e CG
onl
y 1
ch
ild
tole
rate
d m
ilk i
n O
FC 1
yr
afte
r fin
ish-
ing
indu
ctio
n ph
ase.
Du
ring
the
indu
ctio
n ph
ase,
27
of
36
(7
5%)
expe
rienc
ed
an
AEs
w
ith
1 or
m
ore
dose
s. Pt
s w
ith
high
er s
IgE
leve
ls h
ad
mor
e se
vere
AEs
. 1
pt
had
GI
Sx a
nd A
. 17
AEs
tre
ated
with
or
al
AH
, 2A
Es
with
or
al A
H a
nd o
ral C
S.
AEs
too
k pl
ace
with
in
crea
sing
do
ses
or
with
a
dose
pr
evi-
ousl
y to
lera
ted.
Dur
-in
g th
e m
aint
enan
ce
phas
e, 5
ana
phyl
ax-
es
wer
e re
gist
ered
. Sx
in
OFC
inv
olve
d:
1 or
gan
syst
em
in:
10 (
53 %
) co
ntro
ls
and
16
(44%
) pt
s in
OIT
gro
up;
2 or
-ga
n sy
stem
s in
: 9
(4
7%)
cont
rols
an
d 20
(56
%)
pts
in O
IT
grou
p.
Mos
t A
Es w
ere
mild
or
mod
-er
ate.
Tabl
e S1
Con
tinue
d
E-37EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Martınez-Botas, 2015, Spain
32
chi
ldre
n (a
ged
4-
7
yrs,
med
ian
age
4.5
yrs
, 6
8%
mal
e)
enro
lled
in:
AG
(n=
25
) an
d CG
(n=
7
/ H
x (+
), SP
T (+
) and
DB
P-CF
C (+
).
CCT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
cow
’s m
ilkB
uild
-up
phas
e: 1
st w
k: p
ts s
tart
ed
with
2.5
mL
of 1
: 1
0 d
ilute
d CM
an
d re
ceiv
ed s
ever
al d
oses
eve
ry
day
up t
o 3
2 m
L of
non
-dilu
ted
CM.
In s
ubse
quen
t w
ks,
only
one
dai
ly
dose
, in
crea
sed
twic
e a
wk
(Mon
-da
y an
d Th
ursd
ay),
star
ting
with
48
m
L of
non
-dilu
ted
CM a
nd g
radu
ally
in
crea
sing
the
dos
e up
to
20
0 m
L.
Med
ian
dura
tion
of th
e O
IT p
roto
col:
8 w
ks.
Follo
w-u
p: 2
4 m
o of
free
die
t.
10
0 %
AG
pts
co
mpl
ete
OD
(2
00
m
l of
CM
) afte
r bui
ld-
up
phas
e an
d m
ain
tain
ed
tole
ranc
e on
a
free
die
t dur
ing
24
mon
ths
of
follo
w-u
p.
CG:
none
sp
onta
-ne
ousl
y to
ler-
ant,
[OFC
(+
)]
10
0 %
AG
pts
co
mpl
ete
OD
(2
00
ml o
f CM
)
Non
e A
Es r
equi
red
i.m.
E no
r ho
spi-
taliz
atio
n.
Dur
ing
the
build
-up
pha
se, 1
95
do
ses
(23
% o
f th
e to
tal
dos-
es)
prod
uced
A
Es:
13
.8%
RC
, 1
7.4
%
cu
tan
eo
us
, 3
3.3
%
GI,
and
48
.7%
A
.6%
of
th
e re
actio
ns w
ere
grad
e 1
, 3
4%
gr
ade
2,
5%
gr
ade
3,
and
55
%
grad
e 4
; no
ne g
rade
5
. 8
8.5
%
of
grad
e 4
A
Es
wer
e m
ild
or
mod
erat
e A
, an
d 6
9%
of
th
em i
n 5
pts
[
clas
sific
atio
n of
Sam
pson
].
Mansouri, 2007
AG
: n=
20
[(
40
% fe
-m
ale)
, mea
n ag
e 5
6 m
o (8
mo-
18
yr
s)];
CG:
n=1
3 [(
31
%
fem
ale)
, m
ean
age
52
m
o (4
mo-
13
yr
s)] /
Hx
(+),
SPT
(+),
sIgE
(+
), D
BPC
FC
(+)
quas
i R
CT
(no
form
al
rand
o-m
isa-
tion)
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
cow
‘ s m
ilk B
uild
-up
phas
e: D
ose
0.0
6 m
g in
-cr
ease
d to
6.4
g/d
ay o
ver
6 m
o; 1
dr
op o
f CM
dilu
ted
in 2
5 d
rops
of
wat
er 0
.06
mg
of C
M;
initi
al d
ose
give
n fo
r 7
day
s, d
oubl
ed e
very
7
days
for
70
day
s, t
hen
20
0 m
l un-
dilu
ted
milk
a d
ay fo
r 6
mo
(Mai
nte-
nanc
e ph
ase)
.
AG
: 1
8/2
0
(90
%)
com
-pl
ee O
D (
20
0
ml/
day)
; CG
: 0
%
spon
tane
-ou
s to
lera
nce
1
0%
dro
p ou
t be
-ca
use
of
seve
re
anap
hyla
ctic
re
-ac
tions
80
% m
ild r
eac-
tions
du
ring
O
D
(nau
sea,
a
bd
om
ina
l pa
in,
thro
at
itchi
ng,
ecze
-m
a,
dysp
nea)
re
sp
on
de
d to
an
tihis
ta-
min
e;
10
%
pts
whe
ezed
, sl
ower
in
-cr
ease
in d
ose
was
em
ploy
ed.
Tabl
e S1
Con
tinue
d
E-38 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Patriarca, 2003, Italy
OIT
gro
up:
59
pts
age
d 3
-55
yrs
, 3
2 c
hild
ren
(54
%) <
16
yr
s (m
ean
age
not g
iv-
en);
25
/59
m
ale
(42
%).
Thes
e 5
9 p
ts
resu
lted
in 6
6
OD
s as
6 o
f 5
9 u
nder
wen
t 1
3 O
D fo
r dif-
fere
nt fo
ods.
CG
: n=
16
ag
ed 5
-29
(N
o fu
rthe
r de
mog
raph
ic
info
rmat
ion)
. Co
ntro
ls w
ere
thos
e pt
s re
fusi
ng O
IT.
Hx
(+),
SPT
(+),
sIgE
(+),
DB
PCFC
(+)
CCT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
CM n
=2
9
(44
%)*
; Eg
g n=
15
(2
3%
)*; A
l-bu
min
n=
3
(4.5
*%);
Fish
n=
11
(1
7%
)*;
Ora
nge
n=2
(3%
)*;
App
le n
=1
(1
.5%
)*;
Corn
n=
1
(1.5
%)*
; B
eans
n=
1
(1.5
%)*
; Pe
anut
n=
1
(1.5
%)*
; Le
ttuc
e n=
1
(1.5
%)*
; Pe
ach
n=1
(1
.5%
)*
Esca
latio
n ph
ase
Milk
D
ilute
d m
ilk
(10
dr
ops
dilu
t-ed
in
1
00
ml
wat
er)
days
1
-18
: 1
-18
drop
s/da
y; p
ure
milk
: day
s 1
9-
13
6: 1
drop
milk
to 1
20
ml;
Egg
dilu
ted
egg
(10
drop
s in
10
0m
l):
days
1-3
3: 1
drop
to
36
dro
ps x
3
pure
egg
: day
34
to
13
9 1
drop
to
50
ml (
1 e
gg);
Fish
(2
5g
cod
boile
d in
50
ml w
ater
): da
ys 1
to 1
65
: 0.0
00
03
3m
g-1
60
g /d
ay;
Mai
nten
ance
pha
se:
Milk
12
0m
l (1
gla
ss) 2
-3x/
wk;
Egg
1 e
gg 2
-3x/
wk;
Fish
16
0g
boile
d co
d, 2
-3x/
wk;
Oth
er fo
ods
2-3
x/w
k;O
D L
ENG
HT:
13
6 d
ays
(milk
); 1
39
da
ys (e
gg);
16
5 d
ays
(fish
)
OD
suc
cess
rat
e 4
5 o
ut o
f 5
4
(83
%)
[ITT
68
%]
in
AG
. N
o pt
s re
ache
d sp
on
tan
eo
us
tole
ranc
e in
CG
.
51
.1%
of
pt
s in
A
G
expe
rien
ced
AEs
(U
, an
gioe
de-
ma,
or
ab
dom
inal
pa
in)
cont
rolle
d by
AH
or
sodi
um
crom
olyn
but
in
9
pts
(16
.7%
) w
ho
stop
ped
OIT
du
e to
the
occ
urre
nce
of s
kin
or G
I (d
iar-
rhea
, vo
miti
ng a
nd
abdo
min
al p
ain)
Sx
not
cont
rolle
d by
A
H o
r so
dium
cro
-m
olyn
.
Patriarca, 2007, Italy
SLIT
gro
up:
n=4
2; 1
8
girls
; age
d 3
-16
yrs
. CG
: n=
10
(4
girls
; age
d 5
-13
yrs
, un
der
stri
ct
elim
inat
ion
diet
for
18
m
o/ H
x (+
), SP
T (+
), sI
gE
(+),
DB
PCFC
(+
)
CCT,
(c
on-
trol
s re
-fu
sed
AIT
)
SLIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
CM (n
=
18
)*; E
gg
(n=
17
)*;
Fish
(n
=9
)*;
Whe
at
(n=
2)*
; A
pple
(n
=1
)*;
Bea
n (n
=1
)*
Milk
(dilu
tion:
10
dro
ps o
f milk
in 1
00
m
l); f
rom
1 d
rops
/day
at
the
begi
n-ni
ng o
f th
e pr
otoc
ol a
nd a
t th
e en
d of
tre
atm
ent
days
17
5-1
77
13
0
ml/
day;
mai
nten
ance
dos
e: 1
30
ml
of m
ilk a
t le
ast
two
or t
hree
tim
es
a w
eek;
Egg
[di
lutio
n: 1
dro
p of
raw
sh
aken
egg
(al
bum
in +
yol
k) in
10
0
ml o
f wat
e]r;
1 d
rops
from
day
s 1
-3
till 1
0 d
rops
day
s 2
2-2
4; t
hen
dilu
-tio
n 1
0 d
rops
of r
aw s
hake
n eg
g (a
l-bu
min
+ y
olk)
in 1
00
ml o
f w
ater
1
drop
s in
day
s 2
5-2
7 t
ill 5
0 m
l day
s 1
66
-16
8; m
aint
enan
ce d
ose:
1 e
gg
at le
ast
two
or t
hree
tim
es a
wee
k;
Cook
ed fi
sh (
boile
d co
d) 0
.00
00
33
m
g da
ys 1
-3 t
ill 1
00
g d
ays
15
4-
15
6;
mai
nten
ance
dos
e: 1
00
g o
f bo
iled
cod
at le
ast t
wic
e a
wk.
OD
was
suc
cess
-fu
l in
3
1/3
6
(85
.7%
) in
SL
IT g
roup
(6
dr
op
out
for
scar
ce
com
-pl
ianc
e)
[ITT
73
%].
No
pts
reac
hed
spon
-ta
neou
s to
ler-
ance
in C
G.
In 1
1/3
6 in
AG
(3
0.5
%)
had
AEs
suc
h as
, U
, vo
miti
ng,
wor
seni
ng
of
A o
r of
ato
p-ic
der
mat
itis,
an
gioe
dem
a,
and
abdo
mi-
nal p
ain
Tabl
e S1
Con
tinue
d
E-39EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
StudyPa
rtec
ipan
ts
char
acte
ris-
tics/
dia
gnos
-tic
cri
teri
a
Des
ign
Act
ive
grou
p vs
co
mpa
r-at
or
Food
al
lerg
en(s
)Im
mun
othe
rapy
Pr
otoc
ol
Clin
ical
out
com
es
OD
OT
DR-
QoL
Adv
erse
eve
nts
/ m
edic
atio
n us
e
SRs
LRs
Syed, 2014, USA 43
pts
in: O
IT
grou
p (n
=2
3,
med
ian
age
10
.4, r
ange
5
–45
yrs
, m
ale
60
%)
cont
rols
(n
=2
0,
med
ian
age
12
, ran
ge
6–2
0 y
rs,
mal
e 4
0%
) /
Hx
(+),
SPT
(+),
sIgE
(+),
DB
PCFC
(+)
CCT
OIT
vs
rout
ine
care
(f
ood
avoi
d-an
ce)
pean
ut D
oses
of p
eanu
t pro
tein
wer
e ad
min
-is
tere
d or
ally
, w
ith d
ose
esca
latio
n ev
ery
2 w
eeks
(as
tol
erat
ed b
y th
e su
bjec
t) f
rom
0.1
mg
up t
o 4
00
0
mg
prot
ein
by 2
4m
o.
In t
he C
G,
no p
t s
uc
ce
ss
ful-
ly
pass
ed
the
OFC
at
2
4m
o (n
one
spon
ta-
neou
s to
ler-
ant)
. In
the
AG
, pt
s w
ith n
o re
-ac
tion
to
OFC
w
ere
defin
ed a
s de
sens
itize
d at
2
4m
o (n
=2
0)
and
avoi
ded
pe
an
ut-
con
-ta
inin
g fo
ods
for
3m
o.
At
27
mo
(afte
r 3
m
o of
A
IT
with
draw
al),
de-
sens
itize
d pt
s un
derw
ent
an-
othe
r O
FC.
Pts
who
re
acte
d w
ere
clas
sifie
d as
no
n-to
lera
nt (
NT,
n=
13
) an
d th
ose
who
did
not
hav
e an
y cl
inic
al a
ller-
gic
reac
tion
wer
e op
erat
iona
lly d
e-fin
ed a
s “i
mm
une
tole
rant
” (IT
, n=
7).
IT p
ts a
b-st
aine
d fr
om O
IT
and
avoi
ded
all
pean
ut-c
onta
in-
ing
food
fo
r an
ad
ditio
nal
3m
o (t
otal
of
6m
o of
av
oida
nce)
an
d w
ere
reas
sess
ed
for
“im
mun
e to
l-er
ance
” w
ith
an
OFC
at
30
mo
(IT,
n=3
).
Sa
fety
pro
file
not a
s-se
ssed
* va
lues
refe
rred
onl
y to
the
activ
e gr
oup
A, a
sthm
a; A
G, a
ctiv
e gr
oup;
AH
, Ant
ihis
tam
ines
; CCT
, con
trol
led
clin
ical
tria
ls; C
G, c
ontr
ol g
roup
; CM
, Cow
s’ m
ilk; C
S, C
ortic
oste
roid
s; D
BPC
F, D
oubl
e bl
ind
plac
ebo
cont
rolle
d fo
od c
halle
nge;
DEW
, Deh
ydra
ted
egg
whi
te; E
, epi
neph
rine
; EPI
T, E
picu
tane
ous
imm
unot
hera
py; F
AQ
L,PB
, Foo
d A
llerg
y Q
ualit
y of
Life
– P
aren
tal B
urde
n Q
uest
ionn
aire
; GI,
gast
roin
test
inal
; HE,
Hen
s’ e
gg; H
x, C
linic
al H
isto
ry; i
.m.,
intr
amus
cula
r; L
Rs,
Loc
al re
actio
ns; m
o, m
onth
; NS,
not
sta
tistic
ally
sig
nific
ant;
nsLT
Ps,
nons
peci
fic L
ipid
Tra
nsfe
r Pr
otei
ns; O
D, O
ral d
esen
sitiz
atio
n; O
FC, o
ral f
ood
chal
leng
e; O
FS, o
roph
aryn
geal
sym
ptom
s; O
IT, O
ral i
mm
unot
hera
py; ;
PPO
IT, p
robi
otic
+
pean
ut O
IT; P
t, pa
rtic
ipan
t; R
, rhi
nitis
; RC,
rhi
noco
njun
ctiv
itis;
RCT
, ran
dom
ized
con
trol
led
tria
l; R
R, r
isk
rate
; SCD
, med
ian
succ
essf
ully
con
sum
ed d
ose;
sIg
E, s
peci
fic Ig
E;
SLIT
, Sub
lingu
al im
mun
othe
rapy
; SPT
, Ski
n Pr
ick
Test
; SR
s, S
yste
mic
reac
tions
; SU
, Sus
tain
ed u
nres
pons
iven
ess;
Sx,
sym
ptom
s; U
, urt
icar
ia; w
k, w
eek.
Tabl
e S1
Con
tinue
d
E-40 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Tabl
e S2
Cri
tical
app
rais
al o
f inc
lude
d R
CTs
(n=
25
) ass
esse
d by
the
Coch
rane
Ris
k of
Bia
s to
ol
Stud
y(A
utho
r, y
ear,
cou
ntry
) A
dequ
ate
sequ
ence
ge
nera
tion
Allo
catio
n co
ncea
lmen
t B
lindi
ng/
patie
nt-
rela
ted
outc
omes
In
com
plet
e ou
tcom
e da
ta a
ddre
ssed
? Fr
ee o
f sel
ectin
g re
port
ing
Free
of o
ther
bi
as*
Ove
rall
risk
of
bias
Ana
gnos
tou,
20
14
, UK
Low
Hig
hH
igh
Low
Low
Low
Hig
h
Bur
ks, 2
01
2, U
SALo
wLo
wLo
w
Low
Low
Low
Low
Cam
initi
, 20
09
, Ita
lyH
igh
Hig
hLo
wLo
wLo
wH
igh
Hig
h
Cam
initi
, 20
15
, Ita
ly
Low
Low
Low
Low
Low
Low
Low
Del
lo Ia
cono
, 20
13
, Ita
lyLo
wH
igh
Hig
hU
ncle
ar
Unc
lear
U
ncle
ar
Hig
h
Dup
ont,
20
10
, Fra
nce
Unc
lear
Unc
lear
Unc
lear
Low
Low
Low
Unc
lear
Enri
que,
20
05
, Spa
inU
ncle
ar
Unc
lear
Lo
wLo
wLo
wH
igh
Hig
h
Escu
dero
, 20
15
, Spa
inLo
wH
igh
Hig
hLo
wLo
wLo
w h
igh
Fern
ande
z-R
ivas
, 20
09
, Spa
inU
ncle
arLo
wLo
wLo
wLo
wLo
w
Unc
lear
Flei
sche
r, 2
01
3, U
SALo
wLo
wLo
wLo
wLo
wLo
wLo
w
Fuen
tes-
Apa
rici
o, 2
01
3, S
pain
Unc
lear
U
ncle
ar
Unc
lear
Lo
wLo
wLo
wU
ncle
ar
Kim
, 20
11
, USA
Unc
lear
Lo
wLo
wLo
wLo
wLo
wLo
w
Lee,
20
13
, Kor
eaLo
wH
igh
Hig
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E-41EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Tabl
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.4
E-42 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Appendix 3.5
Figure S1 Subgroup analysis RR of food allergy after OIT (only LRB and URB studies) (random-effects model). Heterogeneity: t2 = 0.000; χ2 = 10.882, df = 11 (P<0.453); I2 =0%; Test for overall effect: Z =
-8.451 (P<0.0001)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Burks 2012 0.057 0.004 0.884 0 / 15 22 / 40 2.23Caminiti 2015 0.011 0.000 1.952 0 / 14 16 / 17 0.62Fuentes-Aparicio 2013 0.236 0.122 0.458 7 / 32 37 / 40 38.33Garcia-Ara 2013 0.057 0.009 0.388 1 / 19 33 / 36 4.59Longo 2008 0.043 0.003 0.706 0 / 30 11 / 30 2.15Mansouri 2007 0.041 0.003 0.619 0 / 13 18 / 20 2.25Martinez-Botas 2015 0.064 0.004 0.933 0 / 7 25 / 25 2.32Martorell 2011 0.259 0.134 0.501 7 / 30 27 / 30 38.47Paino 2010 0.048 0.003 0.746 0 / 15 10 / 15 2.21Patriarca 2003 0.039 0.003 0.597 0 / 16 45 / 59 2.24Skripak 2008 0.070 0.005 1.031 0 / 7 12 / 13 2.31Varshney 2011 0.061 0.004 0.910 0 / 9 16 / 19 2.28
0.171 0.114 0.258 15 / 207 272 / 3440.01 0.1 1 10 100
Favours experimental Favours control
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Fernandez-Rivas 2009 0.695 0.295 1.641 5 / 19 14 / 37 46.04Fleischer 2013 0.214 0.073 0.632 3 / 20 14 / 20 39.93Kim 2011 0.065 0.004 0.957 0 / 7 11 / 11 14.03
0.312 0.099 0.978 8 / 46 39 / 68
0.01 0.1 1 10 100
Favours experimental Favours control
Figure S2 Subgroup analysis RR of food allergy after SLIT (only LRB and URB studies) (random-effects model). Heterogeneity: t2 = 0.547; χ2 = 4.623, df = 2 (P<0.099); I2 =57%; Test for overall effect: Z =
-1.998 (P<0.046)
E-43EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Anagnostou 2014 0.017 0.001 0.277 0 / 46 24 / 39 3.06Caminiti 2009 0.183 0.013 2.528 0 / 3 7 / 10 3.30Caminiti 2015 0.011 0.000 1.952 0 / 14 16 / 17 1.08Dello Lacono 2013 1.000 0.022 45.635 1 / 10 1 / 10 1.85Enrique 2005 0.218 0.030 1.588 1 / 11 5 / 12 4.70Escudero 2015 0.035 0.005 0.238 1 / 31 28 / 30 4.85Fernandez-Rivas 2009 0.695 0.295 1.641 5 / 19 14 / 37 8.77Garcia-Ara 2013 0.057 0.009 0.388 1 / 19 33 / 36 4.91Lee 2013 0.045 0.003 0.688 0 / 12 14 / 16 3.12Longo 2008 0.043 0.003 0.706 0 / 30 11 / 30 3.02Mansouri 2007 0.041 0.003 0.619 0 / 13 18 / 20 3.12Martinez-Botas 2015 0.064 0.004 0.933 0 / 7 25 / 25 3.19Martorell 2011 0.259 0.134 0.501 7 / 30 27 / 30 9.54Meglio 2013 0.250 0.070 0.897 2 / 10 8 / 10 7.06Morisset 2007b 0.692 0.468 1.023 18 / 39 34 / 51 10.41Paino 2010 0.048 0.003 0.746 0 / 15 10 / 15 3.08Patriarca 1998 0.055 0.004 0.826 0 / 10 12 / 14 3.14Patriarca 2003 0.039 0.003 0.597 0 / 16 45 / 59 3.11Patriarca 2007 0.054 0.004 0.806 0 / 10 36 / 42 3.15Skripak 2008 0.070 0.005 1.031 0 / 7 12 / 13 3.18Staden 2007 0.722 0.347 1.504 7 / 21 12 / 26 9.26Syed 2014 0.028 0.002 0.433 0 / 20 20 / 23 3.09
0.152 0.086 0.269 43 / 393 412 / 5650.01 0.1 1 10 100
Favours experimental Favours control
Figure S3 Sensitivity analysis RR of food allergy after OIT or SLIT (diagnosis of food allergy confirmed by DBPCFC) (random-effects model). Heterogeneity: t2 = 0.773; χ2 = 55.513, df = 21 (P<0.0001); I2 =62%;
Test for overall effect: Z = -6.480 (P<0.0001)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Anagnostou 2014 0.017 0.001 0.277 0 / 46 24 / 39 2.82Burks 2012 0.057 0.004 0.884 0 / 15 22 / 40 2.86Caminiti 2009 0.183 0.013 2.528 0 / 3 7 / 10 3.06Caminiti 2015 0.011 0.000 1.952 0 / 14 16 / 17 0.96Dello Lacono 2013 1.000 0.022 45.635 1 / 10 1 / 10 1.67Escudero 2015 0.035 0.005 0.238 1 / 31 28 / 30 4.64Fleischer 2013 0.214 0.073 0.632 3 / 20 14 / 20 7.99Fuentes-Aparicio 2013 0.236 0.122 0.458 7 / 32 37 / 40 10.08Garcia-Ara 2013 0.057 0.009 0.388 1 / 19 33 / 36 4.70Kim 2011 0.065 0.004 0.957 0 / 7 11 / 11 2.95Lee 2013 0.045 0.003 0.688 0 / 12 14 / 16 2.89Longo 2008 0.043 0.003 0.706 0 / 30 11 / 30 2.79Mansouri 2007 0.041 0.003 0.619 0 / 13 18 / 20 2.89Martinez-Botas 2015 0.064 0.004 0.933 0 / 7 25 / 25 2.95Martorell 2011 0.259 0.134 0.501 7 / 30 27 / 30 10.08Meglio 2013 0.250 0.070 0.897 2 / 10 8 / 10 7.07Morisset 2007b 0.692 0.468 1.023 18 / 39 34 / 51 11.21Paino 2010 0.048 0.003 0.746 0 / 15 10 / 15 2.85Patriarca 1998 0.055 0.004 0.826 0 / 10 12 / 14 2.90Skripak 2008 0.070 0.005 1.031 0 / 7 12 / 13 2.94Staden 2007 0.722 0.347 1.504 7 / 21 12 / 26 9.72
0.159 0.094 0.271 47 / 391 376 / 5030.01 0.1 1 10 100
Favours experimental Favours control
Figure S4 Risk ratios (RR) of persisting food allergy as assessed by DBPCFC in OIT or SLIT v. controls (Children’s studies). Heterogeneity: t2 = 0.617; χ2 = 51.024, df = 20 (P<0.0001); I2 =61%; Test for overall
effect: Z = -6.773 (P<0.0001)
E-44 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Enrique 2005 0.218 0.030 1.588 1 / 11 5 / 12 18.97Fernandez-Rivas 2009 0.695 0.295 1.641 5 / 19 14 / 37 81.03
0.558 0.229 1.360 6 / 30 19 / 49
0.01 0.1 1 10 100
Favours experimental Favours control
Figure S5 Risk ratios (RR) of persisting food allergy as assessed by DBPCFC in SLIT v. controls (Adult studies) (random-effects model). Heterogeneity: t2 = 0.063; χ2 = 1.104, df = 1 (P<0.293); I2 =9%; Test for
overall effect: Z = -1.283 (P<0.200)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Patriarca 2003 0.039 0.003 0.597 0 / 16 45 / 59 33.21Patriarca 2007 0.054 0.004 0.806 0 / 10 36 / 42 33.79Syed 2014 0.028 0.002 0.433 0 / 20 20 / 23 32.99
0.039 0.008 0.188 0 / 46 101 / 124
0.01 0.1 1 10 100
Favours experimental Favours control
Figure S6 Risk ratios (RR) of persisting food allergy as assessed by DBPCFC in OIT v. controls (Mixed population studies). Heterogeneity: t2 = 0.000; χ2 = 0.110, df = 2 (P<0.946); I2 =0%; Test for overall effect:
Z = -4.042 (P<0.0001)
Study name Statistics for each study Risk ratio and 95% CI
Risk Lower Upper ratio limit limit
Anagnostou 2014 0.017 0.001 0.277Burks 2012 0.057 0.004 0.884Caminiti 2009 0.183 0.013 2.528Caminiti 2015 0.011 0.000 1.952Dello Lacono 2013 1.000 0.022 45.635Escudero 2015 0.035 0.005 0.238Fleischer 2013 0.214 0.073 0.632Fuentes-Aparicio 2013 0.236 0.122 0.458Garcia-Ara 2013 0.057 0.009 0.388Kim 2011 0.065 0.004 0.957Lee 2013 0.045 0.003 0.688Mansouri 2007 0.041 0.003 0.619Meglio 2013 0.250 0.070 0.897Paino 2010 0.048 0.003 0.746Patriarca 2003 0.039 0.003 0.597Patriarca 2007 0.054 0.004 0.806Skripak 2008 0.070 0.005 1.031Staden 2007 0.722 0.347 1.504Syed 2014 0.028 0.002 0.433Varshney 2011 0.061 0.004 0.910
0.118 0.067 0.2090.01 0.1 1 10 100
Favours experimental Favours control
Figure S7 Risk ratios (RR) of persisting food allergy as assessed by DBPCFC in OIT or SLIT v. controls (AIT protocol: Conventional). Heterogeneity: t2 = 0.530; χ2 = 32.445, df = 19 (P<0.028); I2 =41%; Test for
overall effect: Z = -7.363 (P<0.0001)
E-45EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Enrique 2005 0.218 0.030 1.588 1 / 11 5 / 12 8.84Fernandez-Rivas 2009 0.695 0.295 1.641 5 / 19 14 / 37 21.41Longo 2008 0.043 0.003 0.706 0 / 30 11 / 30 5.20Martinez-Botas 2015 0.064 0.004 0.933 0 / 7 25 / 25 5.53Martorell 2011 0.259 0.134 0.501 7 / 30 27 / 30 24.71Morisset 2007b 0.692 0.468 1.023 18 / 39 34 / 51 28.89Patriarca 1998 0.055 0.004 0.826 0 / 10 12 / 14 5.42
0.325 0.162 0.650 31 / 146 128 / 1990.01 0.1 1 10 100
Favours experimental Favours control
Figure S8 Risk ratios (RR) of persisting food allergy as assessed by DBPCFC in OIT or SLIT v. controls (AIT protocol: Rush) (random-effects model). Heterogeneity: t2 = 0.395; χ2 = 15.479, df = 6 (P<0.017); I2
=61%;Test for overall effect: Z = -3.174 (P<0.002)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Caminiti 2009 0.183 0.013 2.528 0 / 3 7 / 10 5.76Garcia-Ara 2013 0.057 0.009 0.388 1 / 19 33 / 36 8.81Lee 2013 0.045 0.003 0.688 0 / 12 14 / 16 5.45Longo 2008 0.043 0.003 0.706 0 / 30 11 / 30 5.27Mansouri 2007 0.041 0.003 0.619 0 / 13 18 / 20 5.45Martinez-Botas 2015 0.064 0.004 0.933 0 / 7 25 / 25 5.57Martorell 2011 0.259 0.134 0.501 7 / 30 27 / 30 18.50Paino 2010 0.048 0.003 0.746 0 / 15 10 / 15 5.37Patriarca 1998 0.055 0.004 0.826 0 / 10 12 / 14 5.47Patriarca 2003 0.039 0.003 0.597 0 / 16 45 / 59 5.42Patriarca 2007 0.054 0.004 0.806 0 / 10 36 / 42 5.49Skripak 2008 0.070 0.005 1.031 0 / 7 12 / 13 5.56Staden 2007 0.722 0.347 1.504 7 / 21 12 / 26 17.87
0.119 0.057 0.249 15 / 193 262 / 3360.01 0.1 1 10 100
Favours experimental Favours control
Figure S9 RR of CMA as assessed by DBPCFC in OIT vs. controls (random-effects model). Heterogeneity: t2 = 0.647; χ2 = 22.521, df = 12 (P<0.032); I2 =47%; Test for overall effect: Z = -5.672 (P<0.0001)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Burks 2012 0.057 0.004 0.884 0 / 15 22 / 40 5.11Caminiti 2015 0.011 0.000 1.952 0 / 14 16 / 17 1.72Dello Lacono 2013 1.000 0.022 45.635 1 / 10 1 / 10 2.99Escudero 2015 0.035 0.005 0.238 1 / 31 28 / 30 8.23Fuentes-Aparicio 2013 0.236 0.122 0.458 7 / 32 37 / 40 17.57Meglio 2013 0.250 0.070 0.897 2 / 10 8 / 10 12.44Morisset 2007b 0.692 0.468 1.023 18 / 39 34 / 51 19.48Patriarca 1998 0.055 0.004 0.826 0 / 10 12 / 14 5.18Patriarca 2003 0.039 0.003 0.597 0 / 16 45 / 59 5.13Patriarca 2007 0.054 0.004 0.806 0 / 10 36 / 42 5.19Staden 2007 0.722 0.347 1.504 7 / 21 12 / 26 16.97
0.218 0.107 0.445 36 / 208 251 / 3390.01 0.1 1 10 100
Favours experimental Favours control
Figure S10 RR of HE allergy as assessed by DBPCFC in OIT vs. controls (random-effects model). Heterogeneity: t2 = 0.642; χ2 = 29.618, df = 10 (P<0.001); I2 =66%; Test for overall effect: Z = -4.182
(P<0.0001)
E-46 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Anagnostou 2014 0.017 0.001 0.277 0 / 46 24 / 39 13.01Fleischer 2013 0.214 0.073 0.632 3 / 20 14 / 20 59.72Kim 2011 0.065 0.004 0.957 0 / 7 11 / 11 13.74Varshney 2011 0.061 0.004 0.910 0 / 9 16 / 19 13.53
0.111 0.039 0.313 3 / 82 65 / 89
0.01 0.1 1 10 100
Favours experimental Favours control
Figure S11 RR of peanut allergy as assessed by DBPCFC in OIT/SLIT vs. controls (random-effects model). Heterogeneity: t2 = 0.166; χ2 = 3.405, df = 3 (P<0.333); I2 =12%; Test for overall effect: Z = -4.154
(P<0.0001)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Anagnostou 2014 0.017 0.001 0.277 0 / 46 24 / 39 3.44Burks 2012 0.057 0.004 0.884 0 / 15 22 / 40 3.49Caminiti 2009 0.183 0.013 2.528 0 / 3 7 / 10 3.73Caminiti 2015 0.011 0.000 1.952 0 / 14 16 / 17 1.17Dello Lacono 2013 1.000 0.022 45.635 1 / 10 1 / 10 2.03Escudero 2015 0.035 0.005 0.238 1 / 31 28 / 30 5.68Fuentes-Aparicio 2013 0.236 0.122 0.458 7 / 32 37 / 40 12.42Lee 2013 0.045 0.003 0.688 0 / 12 14 / 16 3.53Longo 2008 0.043 0.003 0.706 0 / 30 11 / 30 3.41Martorell 2011 0.259 0.134 0.501 7 / 30 27 / 30 12.43Meglio 2013 0.250 0.070 0.897 2 / 10 8 / 10 8.68Morisset 2007b 0.692 0.468 1.023 18 / 39 34 / 51 13.84Paino 2010 0.048 0.003 0.746 0 / 15 10 / 15 3.48Patriarca 1998 0.055 0.004 0.826 0 / 10 12 / 14 3.54Skripak 2008 0.070 0.005 1.031 0 / 7 12 / 13 3.60Staden 2007 0.722 0.347 1.504 7 / 21 12 / 26 11.98Varshney 2011 0.061 0.004 0.910 0 / 9 16 / 19 3.56
0.178 0.099 0.321 43 / 334 291 / 4100.01 0.1 1 10 100
Favours experimental Favours control
Figure S12 Sensitivity analysis RR of food allergy after OIT (only RCTs) (random-effects model). Heterogeneity: t2 = 0.608; χ2 = 42.676, df = 16 (P<0.0001); I2 =62%; Test for overall effect: Z = -5.760
(P<0.0001)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Enrique 2005 0.218 0.030 1.588 1 / 11 5 / 12 15.60Fernandez-Rivas 2009 0.695 0.295 1.641 5 / 19 14 / 37 41.16Fleischer 2013 0.214 0.073 0.632 3 / 20 14 / 20 33.69Kim 2011 0.065 0.004 0.957 0 / 7 11 / 11 9.54
0.311 0.127 0.764 9 / 57 44 / 80
0.01 0.1 1 10 100
Favours experimental Favours control
Figure S13 Sensitivity analysis RR of food allergy after SLIT (only RCTs) (random-effects model). Heterogeneity: t2 = 0.317; χ2 = 4.931, df = 3 (P<0.177); I2 =39%; Test for overall effect: Z = -2.548
(P<0.0001)
E-47EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Caminiti 2015 1.200 0.939 1.534 14 / 14 14 / 17 20.92Lee 2013 1.127 0.900 1.412 12 / 12 14 / 16 24.86Mansouri 2007 1.227 0.961 1.568 13 / 13 16 / 20 21.02Paino 2010 1.240 0.943 1.631 15 / 15 12 / 15 16.84Varshney 2011 0.993 0.753 1.312 8 / 9 17 / 19 16.36
1.157 1.034 1.295 62 / 63 73 / 87
0.5 1 2
Favours experimental Favours control
Figure S14 Safety data – absence of systemic reactions during OIT for food allergy (random-effects model). Heterogeneity: t2 = 0.000; χ2 = 1.761, df = 4 (P<0.780); I2 =0%; Test for overall effect: Z = 2.542
(P<0.011)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Enrigue 2005 0.992 0.770 1.277 10 / 11 11 / 12 33.98Fernandez-Rivas 2009 0.974 0.812 1.167 17 / 19 34 / 37 66.02
0.980 0.845 1.135 27 / 30 45 / 49
0.5 1 2
Favours experimental Favours control
Figure S15 Safety data – absence of systemic reactions during SLIT for food allergy (random-effects model). Heterogeneity: t2 = 0.000; χ2 = 0.013, df = 1 (P<0.908); I2 =0%; Test for overall effect: Z = -0.271
(P<0.786)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Caminiti 2015 1.200 0.939 1.534 14 / 14 14 / 17 18.64Fernandez-Rivas 2009 0.974 0.812 1.167 17 / 19 34 / 37 32.71Mansouri 2007 1.227 0.961 1.568 13 / 13 16 / 20 18.73Paino 2010 1.240 0.943 1.631 15 / 15 12 / 15 15.16Varshney 2011 0.993 0.753 1.312 8 / 9 17 / 19 14.75
1.100 0.986 1.227 67 / 70 93 / 108
0.5 1 2
Favours experimental Favours control
Figure S16 Safety data – absence of systemic reactions during OIT or SLIT for food allergy (only LRB and URB studies). Heterogeneity: t2 = 0.001; χ2 = 4.235, df = 4 (P<0.375); I2 =5%; Test for overall effect: Z =
1.713 (P<0.087)
E-48 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Caminiti 2015 1.200 0.939 1.534 14 / 14 14 / 17 27.84Mansouri 2007 1.227 0.961 1.568 13 / 13 16 / 20 27.97Paino 2010 1.240 0.943 1.631 15 / 15 12 / 15 22.41Varshney 2011 0.993 0.753 1.312 8 / 9 17 / 19 21.78
1.167 1.026 1.329 50 / 51 59 / 71
0.5 1 2
Favours experimental Favours control
Figure S17 Safety data – absence of systemic reactions during OIT for food allergy (only LRB and URB studies) (random-effects model). Heterogeneity: t2 = 0.000; χ2 = 1.691, df = 3 (P<0.639); I2 =0%; Test for
overall effect: Z = 2.341 (P<0.019)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Lee 2013 1.127 0.900 1.412 12 / 12 14 / 16 39.64Mansouri 2007 1.227 0.961 1.568 13 / 13 16 / 20 33.52Paino 2010 1.240 0.943 1.631 15 / 15 12 / 15 26.85
1.190 1.033 1.371 40 / 40 42 / 51
0.5 1 2
Favours experimental Favours control
Figure S18 Safety data – absence of systemic reactions during OIT for CMA (random-effects model). Heterogeneity: t2 = 0.000; χ2 = 0.369, df = 2 (P<0.831); I2 =0%; Test for overall effect: Z = 2.402
(P<0.016)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Caminiti 2015 1.200 0.939 1.534 14 / 14 14 / 17 20.92Lee 2013 1.127 0.900 1.412 12 / 12 14 / 16 24.86Mansouri 2007 1.227 0.961 1.568 13 / 13 16 / 20 21.02Paino 2010 1.240 0.943 1.631 15 / 15 12 / 15 16.84Varshney 2011 0.993 0.753 1.312 8 / 9 17 / 19 16.36
1.157 1.034 1.295 62 / 63 73 / 87
0.5 1 2
Favours experimental Favours control
Figure S19 Safety data – absence of systemic reactions during OIT for food allergy. RR, risk ratio (Children’s studies). Heterogeneity: t2 = 0.000; χ2 = 1.761, df = 4 (P<0.780); I2 =0%; Test for overall effect: Z = 2.549
(P<0.011)
E-49EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Enrigue 2005 0.992 0.770 1.277 10 / 11 11 / 12 33.98Fernandez-Rivas 2009 0.974 0.812 1.167 17 / 19 34 / 37 66.02
0.980 0.845 1.135 27 / 30 45 / 49
0.5 1 2
Favours experimental Favours control
Figure S20 Safety data – absence of systemic reactions during SLIT for food allergy. RR, risk ratio (Adults studies). Heterogeneity: t2 = 0.000; χ2 = 0.013, df = 1 (P<0.908); I2 =0%; Test for overall effect: Z =
-0.271 (P<0.786)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Burks 2012 3.556 1.897 6.665 12 / 15 9 / 40 13.02Caminiti 2015 1.123 0.912 1.382 14 / 14 15 / 17 19.22Mansouri 2007 4.500 1.972 10.270 13 / 13 4 / 20 10.31Martorell 2011 4.692 2.366 9.308 30 / 30 6 / 30 12.19Meglio 2013 3.000 1.251 7.194 10 / 10 3 / 10 9.72Morisset 2007b 1.154 1.027 1.297 39 / 39 44 / 51 20.02Paino 2010 1.824 1.141 2.914 15 / 15 8 / 15 15.51
2.138 1.466 3.116 133 / 136 89 / 183
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
Figure S21 Sensitivity analysis. Safety data – absence of local reactions during OIT for food allergy (random-effects model). Heterogeneity: t2 = 0.181; χ2 = 43.261, df = 6 (P<0.0001); I2 =86%; Test for overall effect:
Z = 3.952 (P<0.0001)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Burks 2012 3.556 1.897 6.665 12 / 15 9 / 40 19.46Caminiti 2015 1.123 0.912 1.382 14 / 14 15 / 17 23.39Mansouri 2007 4.500 1.972 10.270 13 / 13 4 / 20 17.12Martorell 2011 4.692 2.366 9.308 30 / 30 6 / 30 18.79Paino 2010 1.824 1.141 2.914 15 / 15 8 / 15 21.24
2.584 1.366 4.890 84 / 87 42 / 122
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
Figure S22 Safety data – absence of local reactions during OIT for food allergy (only LRB and URB studies) (random-effects model). Heterogeneity: t2 = 0.441; χ2 = 32.816, df = 4 (P<0.0001); I2 =88%; Test for
overall effect: Z = 2.918 (P<0.004)
E-50 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Burks 2012 3.556 1.897 6.665 12 / 15 9 / 40 13.52Caminiti 2015 1.123 0.912 1.382 14 / 14 15 / 17 20.48Lee 2013 6.000 1.576 22.844 9 / 12 2 / 16 5.76Martorell 2011 4.692 2.366 9.308 30 / 30 6 / 30 12.61Meglio 2013 3.000 1.251 7.194 10 / 10 3 / 10 9.95Morisset 2007b 1.154 1.027 1.297 39 / 39 44 / 51 21.41Paino 2010 1.824 1.141 2.914 15 / 15 8 / 15 16.27
2.077 1.429 3.019 129 / 135 87 / 179
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
Figure S23 Safety data – absence of local reactions during OIT for food allergy (only RCTs) (random-effects model). Heterogeneity: t2 = 0.166; χ2 = 39.390, df = 6 (P<0.0001); I2 =85%; Test for overall effect: Z =
3.832 (P<0.0001)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Lee 2013 6.000 1.576 22.844 9 / 12 2 / 16 14.08Mansouri 2007 4.500 1.972 10.270 13 / 13 4 / 20 24.04Martorell 2011 4.692 2.366 9.308 30 / 30 6 / 30 27.80Paino 2010 1.824 1.141 2.914 15 / 15 8 / 15 34.09
3.484 1.887 6.434 67 / 70 20 / 81
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
Figure S24 Safety data – absence of local reactions during OIT for CMA (random-effects model). Heterogeneity: t2 = 0.230; χ2 = 7.886, df = 3 (P<0.048); I2 =62%; Test for overall effect: Z = 3.990
(P<0.0001)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Lee 2013 6.000 1.576 22.844 9 / 12 2 / 16 20.57Martorell 2011 4.692 2.366 9.308 30 / 30 6 / 30 36.56Paino 2010 1.824 1.141 2.914 15 / 15 8 / 15 42.87
3.291 1.498 7.233 54 / 57 16 / 61
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
Figure S25 Safety data – absence of local reactions during OIT for CMA (only RCTs) (random-effects model). Heterogeneity: t2 = 0.319; χ2 = 6.552, df = 2 (P<0.038); I2 =69%; Test for overall effect: Z = 2.966
(P<0.003)
E-51EAACISupplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Burks 2012 3.556 1.897 6.665 12 / 15 9 / 40 17.46Caminiti 2015 1.123 0.912 1.382 14 / 14 15 / 17 34.02Meglio 2013 3.000 1.251 7.194 10 / 10 3 / 10 11.55Morisset 2007b 1.154 1.027 1.297 39 / 39 44 / 51 36.97
1.554 1.089 2.216 75 / 78 71 / 118
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
Figure S26 Safety data – absence of local reactions during OIT for HEA (random-effects model). Heterogeneity: t2 = 0.085; χ2 = 16.513, df = 3 (P<0.001); I2 =81%;Test for overall effect: Z = 2.432
(P<0.015)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Burks 2012 3.556 1.897 6.665 12 / 15 9 / 40 17.83Caminiti 2015 1.123 0.912 1.382 14 / 14 15 / 17 22.11Lee 2013 6.000 1.576 22.844 9 / 12 2 / 16 10.10Mansouri 2007 4.500 1.972 10.270 13 / 13 4 / 20 15.41Meglio 2013 3.000 1.251 7.194 10 / 10 3 / 10 14.82Paino 2010 1.824 1.141 2.914 15 / 15 8 / 15 19.74
2.575 1.457 4.550 73 / 79 41 / 118
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
Figure S27 Safety data – absence of local reactions during OIT for food allergy. RR, risk ratio (AIT protocol: Conventional). Heterogeneity: t2 = 0.370; χ2 = 28.715, df = 5 (P<0.0001); I2 =82%; Test for overall effect:
Z = 3.256 (P<0.001)
Study name Statistics for each study Events / Total Risk ratio and 95% CI
Risk Lower Upper Relative ratio limit limit Control Experimental weight
Martorell 2011 4.692 2.366 9.308 30 / 30 6 / 30 46.99Morisset 2007b 1.154 1.027 1.297 39 / 39 44 / 51 53.01
2.231 0.566 8.797 69 / 69 50 / 81
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
Figure S28 Safety data – absence of local reactions during OIT for food allergy. RR, risk ratio (AIT protocol: Rush) (random-effects model). Heterogeneity: t2 = 0.921; χ2 = 15.657, df = 1 (P<0.0001); I2 =94%; Test
for overall effect: Z = 1.146 (P<0.252)
E-52 EAACI Supplementary materials
Immunotherapy for IgE-mediated food allergy: a review
Appendix 3.6 PRISMA ChecklistSection/topic # Checklist item Reported on
page #
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. 65
ABSTRACT
Structured summary
2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
67
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. 68
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
68
METHODS
Protocol and registration
5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
69
Eligibility criteria
6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.
68-69
Information sources
7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
68
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
E15-16
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).
68-70
Data collection process
10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
69
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
69
Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
69
Summary measures
13 State the principal summary measures (e.g., risk ratio, difference in means). 69
Synthesis of results
14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.
69
Risk of bias across studies
15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
69
Additional analyses
16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
69
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Immunotherapy for IgE-mediated food allergy: a review
Section/topic # Checklist item Reported on page #
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
69-70
Study characteristics
18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
71-72, E17-39
Risk of bias within studies
19 Present data on risk of bias of each study and, if available, any outcome-level assessment (see Item 12).
73, E40-41
Results of individual studies
20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group and (b) effect estimates and
confidence intervals, ideally with a forest plot.
E17-39
Synthesis of results
21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.
74-78
Risk of bias across studies
22 Present results of any assessment of risk of bias across studies (see Item 15). 73
Additional analysis
23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression) (see Item 16).
73, 76, E42-51
DISCUSSION
Summary of evidence
24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., health care providers, users,
and policy makers).
79
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review level (e.g., incomplete retrieval of identified research, reporting bias).
79
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.
80
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
81
