ORIGINAL ARTICLE Updating the role played by immunotherapy for allergic rhinitis: meta-analysis Cemal Cingi, MD 1 , Nuray Bayar Muluk, MD 2 , Deniz Hanci, MD 3 , Seckin Ulusoy, MD 4 and Fezan Sahin, PhD 5 Background: Although the effectiveness of allergen monotherapy immunotherapy for allergic rhinitis (AR) has been well established by many prior studies, other aspects of immunotherapy are still incompletely documented by high-quality studies. The many published papers describe various results. The aim of the present study was to con- duct a meta-analysis on the effectiveness of allergen im- munotherapy. Methods: A total of 56 homogeneous studies were included in the analysis. The inclusion criteria used to select articles were as follows: (1) placebo-controlled clinical trials; (2) the use of immunotherapy; (3) participants and/or physicians were or were not blinded to immunotherapy or placebo assignment (single-blinding, double-blinding, or no-blinding studies); and (4) randomization or not of those in the im- munotherapy and placebo groups. Results: Between 2003 and 2013, 114 placebo-controlled clinical trials were reported in Medline. Studies describing recovery rates in immunotherapy and placebo groups num- bered 56. The distribution of such works was homogeneous (heterogeneity chi-square = 16.11; degrees of freedom [df] = 55; p = 1.000). The extent of recovery in immunotherapy groups was 53.671-fold greater than in placebo groups (Mantel-Haenszel [M-H] pooled risk ra- tio [RR] = 53.671; 95% confidence interval [CI], 36.981 to 77.893; z = 20.96; p < 0.001). Conclusion: Our meta-analysis suggests that immunother- apy is associated with a recovery rate 53.671-fold that of placebo. C 2014 ARS-AAOA, LLC. Key Words: meta-analysis; immunotherapy; allergic rhinitis; placebo- controlled clinical trials; recovery rate. How to Cite this Article: Cingi C, Muluk NB, Hanci D, Ulusoy S, Sahin F. Updat- ing the role played by immunotherapy for allergic rhinitis: meta-analysis. Int Forum Allergy Rhinol. 2014;XX:1–37. A llergen immunotherapy features repeated administra- tion of allergen extracts seeking to reduce symptoms experienced on subsequent allergen exposure, improving the quality of life (QoL) and inducing long-term tolerance. To be effective, immunotherapy requires careful patient se- lection. Immunotherapy is safe if adequate precautions are taken. A decision to use immunotherapy depends on sev- 1 Department of Otorhinolaryngology, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, Turkey; 2 Department of Otorhinolaryngology, Medical Faculty, Kirikkale University, Kirikkale, Turkey; 3 Ear Nose and Throat (ENT) Department, Liv Hospital, Istanbul, Turkey; 4 ENT Clinics, Gaziosmanpas ¸a Taksim Education and Research Hospital, Istanbul, Turkey; 5 Department of Biostatistics, Medical Faculty, Eskisehir Osmangazi University, Eskisehir, Turkey Correspondence to: Nuray Bayar Muluk, MD, Birlik Mahallesi, Zirvekent 2. Etap Sitesi, C-3 blok, No: 62/43, 06610 C ¸ ankaya, Ankara, Turkey; e-mail: [email protected]; [email protected]Potential conflict of interest: None provided. Received: 26 August 2014; Revised: 8 October 2014; Accepted: 10 October 2014 DOI: 10.1002/alr.21447 View this article online at wileyonlinelibrary.com. eral personal and organizational factors, which determine whether 1 type of immunotherapy is more suitable than another (eg, subcutaneous immunotherapy [SCIT] vs sub- lingual immunotherapy [SLIT]). 1 Allergen immunotherapy should be considered for pa- tients who have measureable specific immunoglobulin E (IgE) antibodies against clinically relevant allergens. A de- cision to commence allergen immunotherapy may depend on several factors, including but not limited to patient- specific preference/acceptability, regime adherence, medi- cation requirements, response to avoidance measures, and adverse effects of medications (D). (See in Appendix 1 and 2). 2 Randomized, prospective, single-blinded or double-blinded, placebo-controlled studies have demon- strated the effectiveness of specific immunotherapies used to treat allergic rhinitis (AR). 3, 4 Prospective, randomized, double-blind, placebo-controlled studies have also demon- strated the utility of specific immunotherapies to treat al- lergic asthma. 5–8 Allergen immunotherapy is effective in many allergic patients, provided appropriate allergy evalu- ation has been conducted. 1 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
37
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O R I G I N A L A R T I C L E
Updating the role played by immunotherapy for allergic rhinitis:meta-analysis
Cemal Cingi, MD1, Nuray Bayar Muluk, MD2, Deniz Hanci, MD3, Seckin Ulusoy, MD4 and Fezan Sahin, PhD5
Background: Although the effectiveness of allergenmonotherapy immunotherapy for allergic rhinitis (AR) hasbeen well established by many prior studies, other aspectsof immunotherapy are still incompletely documented byhigh-quality studies. The many published papers describevarious results. The aim of the present study was to con-duct a meta-analysis on the effectiveness of allergen im-munotherapy.
Methods: A total of 56 homogeneous studies were includedin the analysis. The inclusion criteria used to select articleswere as follows: (1) placebo-controlled clinical trials; (2) theuse of immunotherapy; (3) participants and/or physicianswere or were not blinded to immunotherapy or placeboassignment (single-blinding, double-blinding, or no-blindingstudies); and (4) randomization or not of those in the im-munotherapy and placebo groups.
Results: Between 2003 and 2013, 114 placebo-controlledclinical trials were reported in Medline. Studies describingrecovery rates in immunotherapy and placebo groups num-
bered 56. The distribution of such works was homogeneous(heterogeneity chi-square = 16.11; degrees of freedom[df] = 55; p = 1.000). The extent of recovery inimmunotherapy groups was 53.671-fold greater than inplacebo groups (Mantel-Haenszel [M-H] pooled risk ra-tio [RR] = 53.671; 95% confidence interval [CI], 36.981 to77.893; z = 20.96; p < 0.001).
How to Cite this Article:Cingi C, Muluk NB, Hanci D, Ulusoy S, Sahin F. Updat-ing the role played by immunotherapy for allergic rhinitis:meta-analysis. Int Forum Allergy Rhinol. 2014;XX:1–37.
A llergen immunotherapy features repeated administra-tion of allergen extracts seeking to reduce symptoms
experienced on subsequent allergen exposure, improvingthe quality of life (QoL) and inducing long-term tolerance.To be effective, immunotherapy requires careful patient se-lection. Immunotherapy is safe if adequate precautions aretaken. A decision to use immunotherapy depends on sev-
1Department of Otorhinolaryngology, Medical Faculty, EskisehirOsmangazi University, Eskisehir, Turkey; 2Department ofOtorhinolaryngology, Medical Faculty, Kirikkale University, Kirikkale,Turkey; 3Ear Nose and Throat (ENT) Department, Liv Hospital, Istanbul,Turkey; 4ENT Clinics, Gaziosmanpasa Taksim Education and ResearchHospital, Istanbul, Turkey; 5Department of Biostatistics, MedicalFaculty, Eskisehir Osmangazi University, Eskisehir, Turkey
Correspondence to: Nuray Bayar Muluk, MD, Birlik Mahallesi, Zirvekent 2.Etap Sitesi, C-3 blok, No: 62/43, 06610 Cankaya, Ankara, Turkey; e-mail:[email protected]; [email protected]
Potential conflict of interest: None provided.
Received: 26 August 2014; Revised: 8 October 2014; Accepted:10 October 2014DOI: 10.1002/alr.21447View this article online at wileyonlinelibrary.com.
eral personal and organizational factors, which determinewhether 1 type of immunotherapy is more suitable thananother (eg, subcutaneous immunotherapy [SCIT] vs sub-lingual immunotherapy [SLIT]).1
Allergen immunotherapy should be considered for pa-tients who have measureable specific immunoglobulin E(IgE) antibodies against clinically relevant allergens. A de-cision to commence allergen immunotherapy may dependon several factors, including but not limited to patient-specific preference/acceptability, regime adherence, medi-cation requirements, response to avoidance measures, andadverse effects of medications (D). (See in Appendix 1and 2).2 Randomized, prospective, single-blinded ordouble-blinded, placebo-controlled studies have demon-strated the effectiveness of specific immunotherapies usedto treat allergic rhinitis (AR).3,4 Prospective, randomized,double-blind, placebo-controlled studies have also demon-strated the utility of specific immunotherapies to treat al-lergic asthma.5–8 Allergen immunotherapy is effective inmany allergic patients, provided appropriate allergy evalu-ation has been conducted.
1 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.
Any response to allergen immunotherapy is antigen-specific and requires appropriate identification and selec-tion of allergens based on patient history, exposure level,and diagnostic test results. Aeroallergen immunotherapyshould be considered for patients who exhibit symptomsof AR, rhinoconjunctivitis, and/or asthma, after naturalexposure to allergens, and for those who develop specificIgE antibodies against relevant allergens. Symptom severityand duration should also be considered when allergen im-munotherapy is planned. Symptom severity may be definedsubjectively or objectively. Time lost from work, visits toemergency departments or physicians, and the responsesto pharmacotherapy are important objective indicators ofallergic disease severity. Symptoms interfering with sleep,work, or school performance must also be considered. Theeffect of symptoms on QoL and the responsiveness to otherforms of therapy, such as allergen avoidance or medication,should also be reviewed when a decision to prescribe aller-gen immunotherapy is contemplated. In addition, allergenimmunotherapy should be considered if patients wish toavoid long-term pharmacotherapy. Unacceptable adverseeffects of medications should favor a decision to initiate al-lergen immunotherapy, which may not be more costly thanpharmacotherapy over a treatment course.9–11
Allergen immunotherapy for AR affords persistent bene-fits even after discontinuation, and reduces the risk of futureasthma.12–19 Coexisting medical conditions should also beconsidered when evaluating a patient who might be a can-didate for allergen immunotherapy. Patients with coexist-ing AR and asthma should be managed using appropriateregimens of allergen avoidance and pharmacotherapy, butmay also benefit from allergen immunotherapy. However,asthma must be stable before allergen immunotherapy iscommenced.20,21
We conducted a meta-analysis to evaluate the effec-tiveness of allergen immunotherapy. In Medline, we per-formed a search using the key phrase “allergic rhinitis andimmunotherapy and clinical study,” and obtained resultsof 114 placebo-controlled clinical trials15,22–134 conductedfrom 2003 to 2013. To ensure a homogeneous distribution,56 works were included in our study (Table 1).
MethodsStudy design
We conducted a meta-analysis of placebo-controlled clin-ical trials performed in line with the recommendations ofthe Quality of Reporting of Meta-Analysis (QUOROM)Statement.135
SearchA comprehensive literature search of the Medline database(March 1964 to January 2014) was conducted using the fol-lowing terms: “allergic rhinitis AND immunotherapy ANDclinical study.” All possible hits were evaluated; we did notimpose language restrictions.
We retrieved a total of 875 papers published from 1964to 2013. Of these, 464 were published between 2003 and2013, and were subjected to meta-analysis. We limited arti-cles to placebo-controlled clinical trials. A total of 114 stud-ies were controlled both clinically and by use of placebo,and were conducted between 2003 and 2013.15,22–134 Toensure a homogeneous distribution of works, we removed58 of these 114 studies. Thus, we ultimately evaluated 56works (Table 1).
SelectionThe following inclusion criteria were used to select arti-cles for meta-analysis: (1) placebo-controlled clinical tri-als; (2) use of immunotherapy; (3) participants and/orphysicians, and/or neither, blinded to immunotherapy orplacebo assignment (single-blinding, double-blinding, orno-blinding); and (4) random or not assignment of partic-ipants to the immunotherapy or placebo groups. Full-textpapers and/or scientific abstracts were included if they metthe above criteria.
We recorded the authors, dates of publication, countriesin which the studies were performed, populations (adultsand/or children), departments that performed the studies,numbers in the immunotherapy and placebo groups, studytypes/blinding regimes, outcomes, recovery data, the num-bers of patients who improved in both the immunother-apy and placebo groups, patient randomization features,the similarity (or otherwise) of baseline characteristics inthe comparative groups, whether patients were blinded,whether healthcare providers were blinded, and whetherpatients treated other than interventionally received othertreatment.
Data analysisStatistical analyses were performed with the aid of Stata11.0 (Stata Corp., College Station, TX) and p < 0.05was considered to be statistically significant. Dichotomousdata are presented as risk ratios (RRs) with 95% confi-dence intervals (CIs). Data were analyzed via fixed effectsMantel-Haenszel (M-H) meta-analysis. Statistical hetero-geneity was assessed using the Q statistic, and p < 0.10 wasconsidered to indicate significant heterogeneity. The effectof such heterogeneity was quantified using the I2 statistic,which measures the extent of inconsistency among stud-ies by calculating the percentages of total variation acrossstudies. The effect of dexamethasone on recovery was as-sessed by construction of a forest plot. Publication bias wasexplored by constructing funnel plots.
ResultsTrial flow
The Medline search identified 875 articles retrieved us-ing “allergic rhinitis AND immunotherapy AND clini-cal study,” published between 1964 and 2013 (Fig. 1).Of these, 411 were excluded. A total of 464 potentially
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 2
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International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 4
Meta-analysis: role of immunotherapy for ARTA
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unol
ogy
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rgy;
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ient
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30;S
LIT
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;pl
aceb
o=
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pect
ive,
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omiz
ed,
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le-b
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rolle
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ase
Istu
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ects
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ualS
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nsto
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ects
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sens
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san
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erm
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ranc
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ight
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duce
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enet
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odifi
catio
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mem
ory
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.
1020
010
YY
YY
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42Sh
amji10
1 ;201
2;UK
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rgy
and
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ical
Imm
unol
ogy;
tota
lpa
tient
s=
221;
imm
unot
hera
py=
166;
plac
ebo
=55
Pros
pect
ive,
rand
omiz
eddo
uble
-blin
dpl
aceb
o-co
ntro
lled
Atim
e-an
ddo
se-d
epen
dent
incr
ease
inse
rum
inhi
bito
ryac
tivity
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oth
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hich
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ecifi
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odie
s
166
166
055
YY
YY
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45Di
dier
117 ;2
011;
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ceAd
ults
18–5
0ye
ars;
Resp
irato
ryDi
seas
esDe
partm
ent;
tota
lpa
tient
s=
633;
imm
unot
hera
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414;
plac
ebo
=21
9
Pros
pect
ive,
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omiz
ed,
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ticen
ter,
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le-b
lind,
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cont
rolle
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ase
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The
mea
nAA
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ced
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.0%
and
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seas
on3
inth
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mon
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mon
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esea
sona
land
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ctiv
etre
atm
ent
grou
ps,r
espe
ctiv
ely,
com
pare
dw
ithth
atin
the
plac
ebo
grou
p.Su
stai
ned
effic
acy
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mon
than
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mon
thpr
esea
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reat
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twith
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llen
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onst
rate
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ion
insy
mpt
oms
and
resc
uem
edic
atio
nus
e.
136
414
021
9Y
YY
YY
(Co
ntin
ued
)
5 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.TA
BLE
1.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
list
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ient
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izat
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ilar
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teri
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inal
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ove
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49Fu
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gy–H
ead
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ient
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lace
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Pros
pect
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ndom
ized
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uble
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aceb
o-co
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lled
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ease
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inth
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ifica
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oved
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and
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ptom
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es.
5151
037
YY
YY
Y
50Ja
mes
142 ;2
011;
UKAd
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ars;
Alle
rgy
and
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ical
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unol
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lpa
tient
s=
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imm
unot
hera
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lace
bo=
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Pros
pect
ive,
ara
ndom
ized
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uble
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aceb
o-co
ntro
lled
Al.G
rass
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othe
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asu
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ulat
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ies
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ntin
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tory
activ
ityag
ains
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that
pers
ists
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atm
ent
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ontin
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nan
dth
atco
uld
acco
untf
orlo
ng-t
erm
clin
ical
tole
ranc
e.
2222
022
YY
YY
Y
51Ri
eche
lman
n144 ;
2010
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tria
Depa
rtmen
tof
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hino
lary
ngol
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imm
unot
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py=
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lace
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pect
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ticen
ter,
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omiz
ed,
plac
ebo-
cont
rolle
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uble
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rgoi
dtre
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entf
or1
year
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lted
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lygr
eate
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ovem
enta
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gher
RQL
scor
es.T
here
spon
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etit
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lerg
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ject
ion
ther
apy
with
mod
ified
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extra
ctis
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riort
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rgic
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itis
ther
apy.
6666
074
YY
YY
Y
52Ne
lson
147 ;2
011;
USA
Adul
ts18
–65
year
s;Di
visi
onof
Alle
rgy
and
Imm
unol
ogy;
tota
lpa
tient
s=
439;
imm
unot
hera
py=
213;
plac
ebo
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5
Pros
pect
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phas
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IT)
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oss-
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with
rela
ted
Pooi
deae
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ses)
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dem
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fect
ive,
gene
rally
safe
,and
wel
lto
lera
ted
inNo
rthAm
eric
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ults
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gras
spo
llen-
indu
ced
ARC
5521
30
225
YY
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Y
(Co
ntin
ued
)
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 6
Meta-analysis: role of immunotherapy for ARTA
BLE
1.
Co
ntin
ued
Stud
ynu
mb
er
inth
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fere
nce
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hor
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apan
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pect
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The
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ptom
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nto
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t24
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ksaf
teri
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ifica
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2020
011
YY
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akin
o171 ;2
010;
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ults
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rtmen
tof
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ical
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tics;
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ifica
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ated
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pect
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1717
015
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emin
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ildre
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partm
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lmon
ary
Dise
ases
and
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ical
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rgol
ogy;
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lpa
tient
s=
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imm
unot
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;pla
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Pros
pect
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omiz
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plac
ebo-
cont
rolle
d
Incr
ease
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resp
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are
asso
ciat
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ithel
evat
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crea
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nic,
alle
rgen
-spe
cific
Treg
resp
onse
sar
eal
soob
serv
edin
child
ren
durin
gSL
IT.
2020
010
YY
Y
(Co
ntin
ued
)
7 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.TA
BLE
1.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
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of
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met
a-an
alys
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(thi
sar
ticl
e)a
Aut
hor
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e;
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tryb
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atio
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udy
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g
Out
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es
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uno
ther
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gro
upP
lace
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gro
up
Rec
ruit
men
t
of
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ive
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ient
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ient
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inal
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69Sr
ivas
tava
206 ;
2009
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iaIn
stitu
teof
Geno
mic
san
dIn
tegr
ativ
eBi
olog
y;to
talp
atie
nts
=99
;im
mun
othe
rapy
(SLI
T)=
61;p
lace
bo=
38
Pros
pect
ive,
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le-b
lind
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ebo-
cont
rolle
d
ITw
ith2
to3
mix
extra
ctfro
mth
esa
me
alle
rgen
grou
pis
effe
ctiv
efo
rins
ect
hype
rsen
sitiv
ity.
6161
038
YY
YY
75Pa
uli22
8 ;200
8;Fr
ance
Adul
ts18
–50
year
s;Un
iver
sity
Hosp
ital;
tota
lpat
ient
s=
134;
imm
unot
hera
py=
99;p
lace
bo=
35
Pros
pect
ive,
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ticen
ter,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
The
rBet
v1-
base
dva
ccin
e(a
llerg
en-s
peci
ficim
mun
othe
rapy
vacc
ine)
was
safe
and
effe
ctiv
ein
treat
ing
birc
hpo
llen
alle
rgy,
and
indu
ced
ahi
ghly
spec
ific
imm
une
resp
onse
.
9999
035
YY
YY
Y
77Pa
nzne
r242 ;C
zech
2008
;Rep
ublic
Child
ren
and
adul
ts7–
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ars;
Depa
rtmen
tof
Imm
unol
ogy
and
Alle
rgol
ogy;
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lpa
tient
s=
154;
imm
unot
hera
py(S
IT)
=41
;pla
cebo
=30
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pect
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ebo-
cont
rolle
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ndom
ized
Itw
asfo
und
that
both
rout
esof
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inis
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nar
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fect
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gto
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ectiv
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inic
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itha
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ptom
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ddr
ugin
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istra
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030
YY
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urtz
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IT=
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lace
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ospe
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uble
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ges
inth
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g,HR
and
FAP
toa
sim
ilare
xten
t.
2121
021
YY
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ntin
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)
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 8
Meta-analysis: role of immunotherapy for AR
TAB
LE1
.C
ont
inue
d
Stud
ynu
mb
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inth
ere
fere
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hor
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dy
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e;
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tryb
Po
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atio
ncSt
udy
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e/
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din
g
Out
com
es
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uno
ther
apy
gro
upP
lace
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gro
up
Rec
ruit
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t
of
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ecut
ive
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ient
s
Pat
ient
rand
om
-
izat
ion
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teri
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inal
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gro
ups
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ient
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ded
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lth
care
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vid
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ded
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tmen
to
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pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
80Gu
imar
aes
Junq
ueir
deQu
eiro
s252 ;
2008
,Bra
zil
Child
ren
and
adul
ts6–
50;L
abor
ator
yof
Alle
rgy
and
Clin
ical
Imm
unol
ogy;
tota
lpa
tient
s=
73;
imm
unot
hera
py=
58;p
lace
bo=
15
Pros
pect
ive,
rand
omiz
eddo
uble
-blin
d,pl
aceb
o-co
ntro
lled
SIT
usin
gDp
text
ract
alon
ew
asef
fect
ive
inre
duci
ngSP
Tre
spon
sean
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Ele
vels
toDe
rp
2al
lerg
en,w
hile
bact
eria
lex
tract
sin
duce
dde
crea
ses
inIg
Ele
vels
tow
hole
Dpte
xtra
ct
5858
015
YY
YeY
Y
82Fr
anci
s259 ;2
008;
UKAd
ults
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7;Al
lerg
yan
dCl
inic
alIm
mun
olog
ySe
ctio
n;To
talp
atie
nts=
18;
imm
unot
hera
py=
12;p
lace
bo=
6
Pros
pect
ive,
rand
omiz
eddo
uble
-blin
d,pl
aceb
o-co
ntro
lled
Gras
spo
llen
imm
unot
hera
pyw
asef
fect
ive
inre
duci
ngov
eral
lsym
ptom
scor
esan
dco
njun
ctiv
alre
activ
ity.I
nth
eac
tive
grou
psi
gnifi
cant
IL-1
0pr
oduc
tion
occu
rred
early
atlo
wal
lerg
endo
ses
and
ata
sim
ilart
ime
asin
hibi
tion
ofla
tesk
inre
spon
ses
at2
to4
wee
ks
1212
06
YY
YY
Y
83M
oren
o-An
cillo
267 ;
2007
;Spa
inCh
ildre
nan
dad
ults
14–5
5;Ho
spita
lVi
rgen
delP
uerto
;to
talp
atie
nts=
100;
Imm
unot
hera
py(S
LIT)
=51
;pla
cebo
=49
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Alle
rgic
sym
ptom
sw
ere
sign
ifica
ntly
decr
ease
din
the
activ
eim
mun
othe
rapy
grou
p(p
=0.
004)
butn
otin
the
plac
ebo
grou
p.On
ce-d
aily
subl
ingu
alim
mun
othe
rapy
with
outu
pdos
ing
was
wel
lto
lera
ted.
5151
049
YY
YY
Y
84de
Blay
270 ;2
007;
Fran
ceCh
ildre
nan
dad
ults
12–4
1ye
ars;
Depa
rtem
entd
ePn
eum
olog
ie;t
otal
patie
nts=
127;
imm
unot
hera
py(S
LIT)
=51
;pla
cebo
=49
Pros
pect
ive,
mul
ticen
ter,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
SLIT
with
ast
anda
rdiz
ed,
high
-dos
e,3-
gras
spo
llen
extra
ctis
safe
and
sign
ifica
ntly
impr
oves
the
clin
ical
scor
ein
patie
nts
with
hay
feve
rand
with
outa
sthm
adu
ring
the
polle
nse
ason
.
5151
049
YY
YY
Y
(Co
ntin
ued
)
9 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.TA
BLE
1.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
ncSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
92Sa
vola
inen
283 ;
2007
;Fin
land
;Ch
ildre
n5–
15ye
ars;
Depa
rtmen
tof
Pulm
onar
yDi
seas
esan
dCl
inic
alAl
lerg
olog
y;to
tal
patie
nts=
30;
imm
unot
hera
py(S
LIT)
=20
;pla
cebo
=10
Pros
pect
ive,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Durin
gSL
IT,I
L-18
and
SLAM
are
upre
gula
ted,
sugg
estin
gth
atth
eTh
2ty
pein
flam
mat
ory
resp
onse
isdo
wnr
egul
ated
durin
gSL
ITby
incr
ease
dTh
1ty
pere
spon
se.
2020
010
YY
YY
Y
93Ta
ham
iler28
8 ;20
07;T
urke
yDe
partm
ento
fOt
olar
yngo
logy
;tot
alpa
tient
s=
137;
imm
unot
hera
py(S
LIT)
=70
;pla
cebo
=67
Pros
pect
ive,
plac
ebo-
cont
rolle
d
Acco
rdin
gto
the
stud
yre
sults
,it
was
foun
dth
ata
grea
ter
impr
ovem
enti
nth
e3
year
sof
SLIT
com
pare
dw
ithth
e2
year
sof
SLIT
whe
nth
eco
mpa
rativ
ere
sults
ofth
eto
tal6
year
sw
ere
exam
ined
.
7070
067
YY
96Ch
arpi
n306 ;2
007;
Fran
ceAd
ults
;Ser
vice
dePn
eum
olog
ie;t
otal
patie
nts=
32;
imm
unot
hera
py(S
IT)
=17
;pla
cebo
=15
Pros
pect
ive,
rand
omiz
eddo
uble
-blin
d,pl
aceb
o-co
ntro
lled
Ast
atis
tical
lysi
gnifi
cant
impr
ovem
ent(
41%
,p<
0.02
)in
the
conj
unct
iviti
ssy
mpt
omsc
ore
was
obse
rved
inac
tivel
ytre
ated
patie
nts
com
pare
dto
the
plac
ebo
grou
pat
the
peak
ofth
e20
01po
llen
seas
on.
617
015
YY
YY
Y
97Ch
akra
borty
310 ;
2006
;Ind
iaAd
ults
20–5
9ye
ars;
Depa
rtmen
tof
Bota
ny;t
otal
patie
nts
=35
;im
mun
othe
rapy
(SIT
)=
18;p
lace
bo=
17
Pros
pect
ive,
rand
omiz
eddo
uble
-blin
d,pl
aceb
o-co
ntro
lled
The
SIT
grou
psh
owed
decr
ease
sof
33.5
%an
d57
%fro
mth
eba
selin
eSM
Ssdu
ring
the
first
and
seco
ndtre
atm
ents
easo
n,re
spec
tivel
y.
1018
017
YY
YY
Y
100
Cret
icos
315 ;2
006;
USA
Adul
ts23
–60
year
s;Di
visi
onof
Alle
rgy
and
Clin
ical
Imm
unol
ogy;
tota
lpat
ient
s=
25;
imm
unot
hera
py(S
LIT)
=14
;pla
cebo
=11
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d,ph
ase
2
Imm
unot
hera
pyw
itha
6-w
eek
regi
men
ofth
ea
ragw
eed-
toll-
like
rece
ptor
9ag
onis
tvac
cine
(AIC
vacc
ine)
appe
ared
toof
ferl
ong-
term
clin
ical
effic
acy
inth
etre
atm
ento
frag
wee
dal
lerg
icrh
initi
s.
1414
011
YY
YY
Y
(Co
ntin
ued
)
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 10
Meta-analysis: role of immunotherapy for AR
TAB
LE1
.C
ont
inue
d
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
ncSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
101
Savo
lain
en31
9 ;20
06;F
inla
ndCh
ildre
nag
ed5–
15ye
ars;
Depa
rtmen
tof
Pulm
onar
yDi
seas
esan
dCl
inic
alAl
lerg
olog
y;to
tal
patie
nts=
30;
imm
unot
hera
py(S
LIT)
=20
;pla
cebo
=10
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d,do
se-
resp
onse
,ph
ase
II
SLIT
indu
ced
ado
se-d
epen
dent
syst
emic
alle
rgen
-spe
cific
imm
unol
ogic
alre
spon
sein
child
ren
with
AR.
2020
010
YY
YY
Y
102
Valo
virta
320 ;2
006;
Finl
and
Child
ren
5–14
year
s;Al
lerg
yCe
ntre
;tot
alpa
tient
s=
88;
imm
unot
hera
py(S
LIT)
=59
;pla
cebo
=29
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
SLIT
with
tree
polle
nex
tract
prov
ided
dose
-dep
ende
ntbe
nefit
sin
tree
polle
n-al
lerg
icch
ildre
nin
term
sof
sign
ifica
ntly
redu
ced
sym
ptom
san
dm
edic
atio
nus
e.Th
etre
atm
entw
asw
ell
tole
rate
d.
5959
029
YY
YY
Y
103
Lars
en32
1 ;200
6;De
nmar
kAd
ults
18–5
0ye
ars;
Alle
rgy
Clin
ic;t
otal
patie
nts=
30;
imm
unot
hera
py(S
LIT)
=23
;pla
cebo
=7
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
The
data
indi
cate
that
ash
ort
dose
incr
ease
phas
em
ayre
duce
the
inci
denc
eof
AEs
whe
nhi
gh-d
ose
SLIT
isad
min
iste
red.
2323
07
YY
YY
Y
105
Pass
alac
qua33
0 ;20
06;I
taly
Adul
ts18
–50
year
s;Al
lerg
yan
dRe
spira
tory
Dise
ases
;to
talp
atie
nts=
56;
imm
unot
hera
py(S
LIT)
=28
;pla
cebo
=28
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
SLIT
was
clin
ical
lyef
fect
ive
and
safe
inm
ite-in
duce
dm
ilddi
seas
e
2828
028
YY
YY
Y
106
Cola
s343 ;2
006;
Spai
nAd
ults
18–5
1ye
ars;
Serv
icio
deAl
ergi
a;to
talp
atie
nts=
60;
imm
unot
hera
py=
41;p
lace
bo=
19
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Imm
unot
hera
pyw
ithth
ism
odifi
edva
ccin
eof
Sals
ola
kali
polle
nis
safe
and
effic
acio
usto
treat
patie
nts
clin
ical
lyse
nsiti
veto
this
polle
n.
4141
019
YY
YY
Y
(Co
ntin
ued
)
11 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.
TAB
LE1
.C
ont
inue
d
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
ncSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
107
Durh
am34
4 ;200
6;UK
Adul
ts18
–65
year
s;Na
tiona
lHea
rtan
dLu
ngIn
stitu
te;t
otal
patie
nts=
855;
imm
unot
hera
py=
705;
plac
ebo
=15
0
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d,m
ultin
atio
nal,
mul
ticen
ter
This
stud
yco
nfirm
sdo
se-d
epen
dent
effic
acy
ofth
egr
ass
alle
rgen
tabl
et.
204
705
015
0Y
YY
YY
108
Frew
353 ;2
006;
UKAd
ults
18–6
0ye
ars;
Alle
rgy
&In
flam
mat
ion
Rese
arch
Subd
ivis
ion;
tota
lpat
ient
s=
410;
imm
unot
hera
py(S
IT)
=30
7;pl
aceb
o=
103
Pros
pect
ive,
doub
le-b
lind,
rand
omiz
ed,
plac
ebo-
cont
rolle
d
One
seas
onof
imm
unot
hera
pyw
ithAl
utar
dgr
ass
polle
nre
duce
dsy
mpt
oms
and
med
icat
ion
use
and
impr
oved
the
qual
ityof
life
ofsu
bjec
tsw
ithm
oder
atel
yse
vere
hay
feve
r.
125
307
010
3Y
YY
YY
111
Jute
l370 ;2
005;
Pola
ndAd
ults
21–3
0ye
ars;
Depa
rtmen
tof
Inte
rnal
Med
icin
ean
dAl
lerg
olog
y;to
tal
patie
nts=
57;
imm
unot
hera
py(S
IT)
=29
;pla
cebo
=28
Pros
pect
ive,
doub
le-b
lind,
rand
omiz
ed,
plac
ebo-
cont
rolle
d
Are
com
bina
ntal
lerg
enva
ccin
eca
nbe
aef
fect
ive
and
safe
treat
men
tto
amel
iora
tesy
mpt
oms
ofal
lerg
icrh
initi
s.
2929
028
YY
YY
Y
112
Amea
l375 ;2
005;
Spai
nCh
ildre
nan
dad
ults
14–4
8ye
ars;
Alle
rgy
Depa
rtmen
t;to
tal
patie
nts=
55;
imm
unot
hera
py(S
IT)
=29
;pla
cebo
=26
Pros
pect
ive,
doub
le-b
lind,
rand
omiz
ed,
plac
ebo-
cont
rolle
d
Afte
r1ye
arof
treat
men
t,th
em
odifi
edex
tract
ofD.
pter
onys
sinu
sde
mon
stra
ted
tobe
safe
and
effic
acio
usto
treat
patie
nts
with
asth
ma
and
alle
rgic
rhin
ocon
junc
tiviti
sse
nsiti
zed
toth
ism
ite.
2929
028
YY
YY
Y
113
Alva
rez-
Cues
ta38
4 ;20
05;S
pain
Adul
ts18
–58
year
s;Se
rvic
iode
Aler
gia;
tota
lpat
ient
s=
53;
imm
unot
hera
py(S
IT)
=25
;pla
cebo
=28
Pros
pect
ive,
doub
le-b
lind,
rand
omiz
ed,
plac
ebo-
cont
rolle
d
ITw
ithde
pigm
ente
d,gl
utar
alde
hyde
-mod
ified
alle
rgen
extra
cts
was
wel
l-tol
erat
edan
dad
ded
bene
ficia
leffe
cts
toAR
treat
men
tin
polle
nal
lerg
icpa
tient
sel
iciti
ngan
impr
ovem
enti
nQO
Len
ough
toju
stify
ach
ange
inth
epa
tient
’stre
atm
ent.
2525
028
YY
YY
Y
(Co
ntin
ued
)
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 12
Meta-analysis: role of immunotherapy for ARTA
BLE
1.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
ncSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
114
Corr
igan
386 ;2
005;
UKAd
ults
18–6
0ye
ars;
Guy’
s,Ki
ng’s
and
StTh
omas
’sSc
hool
ofM
edic
ine;
tota
lpa
tient
s=
154;
imm
unot
hera
py=
77;p
lace
bo=
77
Pros
pect
ive,
doub
le-b
lind,
mul
ticen
trepl
aceb
o-co
ntro
lled,
phas
e3
clin
ical
trial
The
gras
spo
llen
alle
rgoi
dw
assh
own
tobe
safe
and
clin
ical
lyef
ficac
ious
inth
em
anag
emen
tofh
ayfe
verw
ithor
with
outa
sthm
a(G
INA
Ior
II).
3677
077
YY
YY
Y
15Po
losa
407 ;2
004;
Italy
Adul
ts20
–54
year
s;Is
titut
odi
Mal
attie
Appa
rato
Resp
irato
rio;t
otal
patie
nts=
30;
imm
unot
hera
py=
15;p
lace
bo=
15
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind
plac
ebo-
cont
rolle
d
Parie
taria
-SIT
redu
ces
sym
ptom
and
resc
uem
edic
atio
nsc
ores
,bu
tno
chan
ges
inBH
Rto
met
hach
olin
eor
sput
umeo
sino
phili
aw
ere
obse
rved
.
1515
015
YY
YY
Y
119
Miro
ne41
1 ;200
4;Ita
lyAd
ults
23–6
0ye
ars;
Dipa
rtim
ento
Mul
tizon
ale
diAl
lerg
olog
iaed
Imm
unol
ogia
Clin
ica;
tota
lpat
ient
s=
30;
imm
unot
hera
py=
14;p
lace
bo=
16
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Inje
ctiv
eim
mun
othe
rapy
issa
fean
dcl
inic
ally
effe
ctiv
ein
Euro
pean
patie
nts
sens
itize
dto
Ambr
osia
1414
016
YY
YY
Y
120
Crim
i414 ;2
004;
Italy
Istit
uto
diM
alat
tiede
ll’Ap
para
toRe
spira
torio
;tot
alpa
tient
s=
30;
imm
unot
hera
py=
15;p
lace
bo=
15
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Arie
taria
-SIT
isef
fect
ive
inco
ntro
lling
hay
feve
rsy
mpt
oms
and
resc
uem
edic
atio
ns,b
utno
chan
ges
inth
eBH
Rto
met
hach
olin
eor
sput
umeo
sino
phili
aw
ere
obse
rved
.
1515
015
YY
YY
Y
122
Bufe
421 ;2
004;
Germ
any
Child
ren
8–9
year
s;Ex
perim
enta
lPn
eum
olog
y;to
tal
patie
nts=
161;
imm
unot
hera
py=
82;p
lace
bo=
79
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d,m
ultic
entre
Inth
isst
udy
SLIT
was
acco
mpa
nied
bya
sign
ifica
ntpl
aceb
oef
fect
.Effi
cacy
oftre
atm
entc
ould
only
bese
enin
child
ren
with
seve
recl
inic
alsy
mpt
oms
and
this
beca
me
clin
ical
lym
arke
daf
ter3
year
sof
ther
apy.
8282
079
YY
YY
Y
(Co
ntin
ued
)
13 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.TA
BLE
1.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
ncSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
123
Tonn
el42
2 ;200
4;Fr
ance
Child
ren
and
adul
ts7–
45ye
ars;
Serv
ice
dePn
eum
olog
ieet
Imm
uno-
Alle
rgol
ogie
;to
talp
atie
nts=
32;
imm
unot
hera
py=
15;p
lace
bo=
17
Pros
pect
ive,
rand
omiz
ed,
plac
ebo-
cont
rolle
d
This
stud
yin
dica
tes
the
supe
riorit
yof
activ
etre
atm
ent
vspl
aceb
o,ev
alua
ted
onef
ficac
ycr
iteria
(rhin
itis
scor
e)or
obje
ctiv
ecr
iteria
(ski
nre
activ
ity).
1515
017
YY
Y
124
van
Neer
ven42
4 ;20
04;D
enm
ark
ALK-
Abel
loto
talp
atie
nts
=42
;im
mun
othe
rapy
=21
;pla
cebo
=21
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Spec
ific
alle
rgy
vacc
inat
ion
(SAV
)le
ads
toan
inhi
bitio
nof
the
S-FA
Pne
eded
toob
tain
optim
alT
cell
activ
atio
nat
the
low
alle
rgen
conc
entra
tions
pres
enti
nvi
vo.
2121
021
YY
YY
Y
125
TePa
s428 ;2
004;
USA
Adul
ts19
–55
year
s;Di
visi
onof
Imm
unol
ogy
and
Alle
rgy,
Depa
rtmen
tof
Pedi
atric
s;to
tal
patie
nts=
23;
imm
unot
hera
py=
12;p
lace
bo=
11
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Oral
imm
unot
hera
pyw
ithm
icro
enca
psul
ated
alle
rgen
indu
ces
afo
rmof
imm
unol
ogic
tole
ranc
eto
the
alle
rgen
and
isa
safe
,ef
ficie
nt,a
ndef
fect
ive
met
hod
ofal
lerg
enim
mun
othe
rapy
.
1212
011
YY
YY
Y
126
Khin
chi43
2 ;200
4;De
nmar
kAd
ults
20–5
8ye
ars;
Alle
rgy
Clin
ic;t
otal
patie
nts=
58;
imm
unot
hera
py(S
LIT,
SCIT
)=39
;pla
cebo
=19
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Base
don
the
limite
dnu
mbe
rof
patie
nts
the
clin
ical
effic
acy
ofSL
ITw
asno
tsta
tistic
ally
diffe
rent
from
SCIT
,and
both
treat
men
tsar
ecl
inic
ally
effe
ctiv
eco
mpa
red
with
plac
ebo
inth
etre
atm
ento
fbi
rch
polle
nrh
inoc
onju
nctiv
itis.
3939
019
YY
YY
Y
127
Pajn
o435 ;2
003;
Italy
Child
ren
8–14
year
s;Pa
edia
tric
Clin
ic;t
otal
patie
nt=
30;
imm
unot
hera
py(S
LIT)
=15
;pla
cebo
=15
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
The
clin
ical
effic
acy
ofSL
IT+
flutic
ason
eis
equa
lto
that
offlu
ticas
one
alon
e,bu
tthe
addi
tion
ofSL
ITha
sef
fect
sal
soon
nonb
ronc
hial
sym
ptom
s.
1515
015
YY
YY
Y
(Co
ntin
ued
)
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 14
Meta-analysis: role of immunotherapy for AR
TAB
LE1
.C
ont
inue
d
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
ncSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
128
Wut
hric
h437 ;2
003;
Switz
erla
ndCh
ildre
n;Al
lerg
yUn
it,De
partm
ento
fDe
rmat
olog
y;to
tal
patie
nts=
20;
imm
unot
hera
py(S
LIT)
=10
;pla
cebo
=10
Pros
pect
ive,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
SLIT
with
agr
ass
polle
nex
tract
isw
ellt
oler
ated
inch
ildre
nan
dis
able
tosi
gnifi
cant
lyre
duce
drug
cons
umpt
ion
durin
gth
ese
cond
year
oftre
atm
ent.
1010
010
YY
YY
132
Polo
sa45
1 ;200
3;Ita
lyAd
ults
20–5
4ye
ars;
Dipa
rtim
ento
diM
edic
ina
Inte
rna
eSp
ecia
listic
a;to
tal
patie
nts=
30;
imm
unot
hera
py=
15;p
lace
bo=
15
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
The
clin
ical
effic
acy
ofPa
rieta
riaSI
Tw
asex
clus
ivel
yas
soci
ated
with
atte
nuat
ion
inse
ason
alw
orse
ning
ofPC
15AM
P,su
gges
ting
that
AMP
may
beus
eful
inm
onito
ring
chan
ges
inal
lerg
icin
flam
mat
ion
ofth
eai
rway
s.
1515
015
YY
YY
Y
133
Andr
e457 ;2
003;
Fran
ceDe
parte
men
tSc
ient
ifiqu
eet
Med
ical
;tot
alpa
tient
s=
92;
imm
unot
hera
py=
43;p
lace
bo=
49
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Durin
gth
ew
hole
perio
dof
polli
natio
n,th
edi
ffere
nce
favo
ring
imm
unot
hera
pyw
ashi
ghly
sign
ifica
ntfo
rthe
glob
alas
sess
men
tby
the
patie
nt(p
=0.
004)
and
byth
ein
vest
igat
or(p
=0.
005)
.Ad
vers
ere
actio
nsw
ere
repo
rted
mor
eof
ten
inth
eac
tive
treat
men
tbut
mild
orm
oder
ate,
and
they
abat
edaf
terd
ose
adju
stm
ent.
4343
049
YY
YY
Y
aTh
enu
mb
ers
of
stud
ies
inth
isco
lum
nar
eth
est
udy
num
ber
sin
the
refe
renc
elis
to
fth
ism
eta-
anal
ysis
.All
56st
udie
sw
ere
clin
ical
and
pla
ceb
o-c
ont
rolle
d,a
ndex
hib
ited
aho
mo
gen
eous
dis
trib
utio
n.bTh
enu
mb
ers
of
the
stud
ies
refe
rto
ato
talo
f46
4p
aper
sin
Med
line
det
ecte
db
yse
arch
ing
wit
hth
eke
yp
hras
e“a
llerg
icrh
init
isan
dim
mun
oth
erap
yan
dcl
inic
alst
udy”
;al
lpap
ers
wer
ep
ublis
hed
bet
wee
n20
03an
d20
13.
c Tw
enty
-six
of
the
revi
ewed
pap
ers
used
SLIT
;7
of
the
revi
ewed
pap
ers
used
SCIT
;an
d2
of
the
revi
ewed
pap
ers
used
bo
thSL
ITan
dSC
IT.
Inth
eo
ther
pap
ers,
the
used
typ
eo
fth
eim
mun
oth
erap
yw
asre
po
rted
asim
mun
oth
erap
yo
rSI
T.A
Ad
SS=
Ave
rag
eA
dju
sted
Sym
pto
mSc
ore
;A
E=
adve
rse
even
t;A
IC=
Am
ba
1-im
mun
ost
imul
ato
ryp
hosp
horo
thio
ate
olig
onu
cleo
tid
eco
njug
ate;
AIT
=al
lerg
yim
mun
oth
erap
yta
ble
t;A
MP
=Ad
eno
sine
5’-
mo
nop
hosp
hate
;AR
=al
lerg
icrh
init
is;A
RC
=A
llerg
icR
hino
conj
unct
ivit
is;A
RM
S=
Ave
rag
eR
escu
eM
edic
atio
nSc
ore
;AR
TSS
=A
vera
ge
Rhi
noco
njun
ctiv
itis
Tota
lSym
pto
mSc
ore
;BH
R=
bro
nchi
alhy
per
resp
ons
iven
ess;
CIS
=C
linic
alIn
dex
Sco
re;C
PT
=C
onj
unct
ival
Pro
voca
tio
nTe
st;D
PT
=D
erm
ato
pha
go
ides
pte
rony
ssin
us;D
PT+
MR
B=
DP
Tal
lerg
en+
mix
edre
spir
ato
ryb
acte
rial
extr
acts
;DR
F=
do
sera
nge-
find
ing
;FA
P=F
acili
tate
dA
llerg
enP
rese
ntat
ion;
GIN
A=
Glo
bal
Init
iati
vefo
rA
sthm
a;H
DM
=ho
use
dus
tm
ite;
HR
=His
tam
ine
Rel
ease
;Ig
=im
mun
og
lob
ulin
;Ig
E-F
AB
=im
mun
og
lob
ulin
E–f
acili
tate
dal
lerg
enb
ind
ing
;IL
=in
terl
euki
n;IR
=Ind
exo
fR
eact
ivit
y;
IT=
imm
uno
ther
apy;
QO
L=
qua
lity
of
life;
RQ
L=
Rhi
niti
s/R
hino
conj
unct
ivit
isQ
ualit
yo
fLi
fe;
RQ
LQ=
Rhi
noco
njun
ctiv
itis
Qua
lity
of
Life
Que
stio
nnai
re;
SCIT
=su
bcu
tane
ous
imm
uno
ther
apy;
SIT
=sp
ecifi
cal
lerg
enim
mun
oth
erap
y;SL
AM
=Sig
nalli
ngly
mp
hocy
tic
acti
vati
on
mo
lecu
le;
SLIT
=su
blin
gua
lim
mun
oth
erap
y;SM
S=
sym
pto
m-m
edic
atio
nsc
ore
;SP
T=s
kin
pri
ckte
st;
Th1
=T
help
er1;
Th2
=T
help
er2;
Treg
=re
gul
ato
ryT
cell.
15 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.
FIGURE 1. Placebo-controlled clinical trials included in meta-analysis.
relevant articles were published between 2003 and 2013.Articles that were neither clinical trials nor placebo-controlled trials were excluded (n = 350). Thus, we iden-tified 114 placebo-controlled clinical trials.15,22–134 To en-sure a homogeneous distribution, studies deviating fromour inclusion criteria were excluded (n = 58) and, ulti-mately, we included 56 placebo-controlled clinical trials inour systematic review (Tables 1 and 2).
OutcomesMeta-analyses of the effects of immunotherapy and placeboin terms of recovery from AR are shown in Table 3. To ob-tain a homogeneous distribution, studies deviating from thenorm were removed from the total of 114 and, ultimately,we included 56 studies that exhibited a homogeneous dis-tribution (heterogeneity chi-squared = 16.11; degrees offreedom [df] = 55; p = 1.000). The extent of patient re-covery in the immunotherapy group was 53.671-fold morethan in the placebo group (M-H pooled RR = 53.671; 95%CI, 36.981 to 77.893; z = 20.96; p < 0.001).
Figure 2 shows a forest plot of the 56 studies includedin the meta-analysis. The central square in each horizontalline represents the RR for each study. The lines demonstratethe ranges of 95% CIs. The vertical line at an RR of 1 isthe line of no effect. “% Weight” indicates the influenceexerted by each study on the pooled RR.
Figure 3 shows the funnel plot of the 56 studies includedin the meta-analysis. The vertical solid line represents the
logarithmic transformation of the overall estimated treat-ment effect (ie, the log [RR]). Diagonal dotted lines repre-sent pseudo-95% CIs for the estimated treatment effects,and the circles represent the treatment effects of each of the56 studies (RR is the risk ratio).
DiscussionThe principal types of immunotherapy are SCIT and SLIT.The success of immunotherapy, as compared to placebo, isbased on the immunological responses to immunotherapy.The immunological response to subcutaneous immunother-apy is characterized by decreases in the sensitivities of end-organs and changes in the humoral and cellular responsesto the administered allergens (A). (See in Appendix 1and 2).136 Reductions in end-organ responses upon im-munotherapy include less prominent early and late re-sponses of the skin, conjunctiva, nasal mucosa, andbronchi to allergen challenge; decreased allergen-inducedeosinophil, basophil, and mast cell infiltration; blunt-ing of mucosal priming; and reduction of nonspecificbronchial sensitivity to histamine (A). (See in Appendix 1and 2).82,136–141
SCIT in patients with pollen rhinitis is associated withtransient increases in allergen-specific IgE levels, blunt-ing of seasonal increases in such levels,142 and increasesin allergen-specific IgG levels (particularly IgG4)141–143
and IgA.141,144 A recent Cochrane systematic review of
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 16
Meta-analysis: role of immunotherapy for ARTA
BLE
2.
Cha
ract
eris
tics
of
pla
ceb
o-c
ont
rolle
dcl
inic
altr
ials
excl
uded
too
bta
ina
hom
og
eneo
usd
istr
ibut
ion
(n=
58)
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
24Pa
tel12
;201
3;Ca
nada
Allie
dRe
sear
chIn
tern
atio
nal;
tota
lpa
tient
s=
228;
spec
ific
imm
unot
hera
pyor
plac
ebo
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d,ph
ase
IIbst
udy
This
stud
yde
mon
stra
ted
that
anul
trash
ortc
ours
eof
Ragw
eed
MAT
AM
PLis
effic
acio
usin
redu
cing
alle
rgy
sym
ptom
sin
patie
nts
with
seas
onal
alle
rgic
rhin
itis
and
that
itis
wel
lto
lera
ted.
YY
YY
Y
26M
urph
y20;2
013;
USA
Adul
ts18
–65
year
s;Bo
ysTo
wn
Natio
nal
Rese
arch
Hosp
ital;
tota
lpat
ient
s=
289;
imm
unot
hera
pyta
blet
(AIT
)=13
9;pl
aceb
o=
150
Pros
pect
ive,
rand
omiz
edpl
aceb
o-co
ntro
lled
trial
2800
BAU
gras
sAI
Tdi
dno
tde
mon
stra
tesi
gnifi
cant
sym
ptom
impr
ovem
entv
spl
aceb
o.
813
99
150
YY
Y
27No
lte21
;201
3;US
AAd
ults
;Mer
ckSh
arp
&Do
hme
Corp
.;to
tal
patie
nts=
565;
AIT;
plac
ebo
Pros
pect
ive,
rand
omiz
ed,
plac
ebo-
cont
rolle
d
Ragw
eed
AIT
was
effe
ctiv
ean
dw
ellt
oler
ated
inra
gwee
d-al
lerg
icNo
rthAm
eric
anad
ults
.
YY
Y
29M
eyer
30;2
013;
Germ
any
Adul
ts;M
edic
alDe
partm
ent
Alle
rgop
harm
aGm
bH&
Co.K
G;to
tal
patie
nts=
37;
imm
unot
hera
py=
30;p
lace
bo=
7
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
The
tota
lsym
ptom
scor
esi
gnifi
cant
lyde
crea
sed
inal
lac
tive
grou
psco
mpa
red
with
plac
ebo.
2430
17
YY
YY
Y
32Bo
zek43
;201
3;Po
land
Adul
ts(E
lder
ly)6
0–75
year
s;De
rmat
olog
yan
dAl
lerg
olog
y;to
tal
patie
nts=
111;
imm
unot
hera
py(S
LIT)
grou
p=
51;p
lace
bo=
57
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
The
tota
lnas
alsy
mpt
omsc
ore
decr
ease
dby
44%
inth
eac
tive
grou
pan
d6%
inth
epl
aceb
ogr
oup
afte
r3ye
ars
ofSL
IT.S
ublin
gual
alle
rgen
-sp
ecifi
cim
mun
othe
rapy
inel
derly
patie
nts
gene
rate
da
sign
ifica
ntcl
inic
alim
prov
emen
tin
the
activ
egr
oup
com
pare
dw
ithth
epl
aceb
ogr
oup,
parti
cula
rlydu
ring
the
heat
ing
seas
on.
2251
357
YY
YY
Y
(Co
ntin
ued
)
17 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.
TAB
LE2
.C
ont
inue
d
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
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ilar
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elin
e
char
ac-
teri
stic
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inal
l
gro
ups
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ient
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ded
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lth
care
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vid
er
blin
ded
Eq
ual
trea
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to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
33Bo
nval
et53
;201
2;Fr
ance
Stal
lerg
enes
;tot
alpa
tient
no:8
9;SL
ITan
dpl
aceb
o
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
SLIT
indu
ced
a29
.3%
impr
ovem
ento
fthe
aver
age
rhin
ocon
junc
tiviti
sto
tal
sym
ptom
scor
ein
the
activ
egr
oup,
whe
nco
mpa
red
toth
epl
aceb
ogr
oup.
YY
YY
Y
34Co
x55;2
012;
USA
Adul
ts;N
ova
Sout
heas
tern
Univ
ersi
ty;t
otal
patie
nts=
473;
imm
unot
hera
py=
233;
plac
ebo
=24
0
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
dst
udy
The
mea
nda
ilyCS
over
the
polle
npe
riod
was
sign
ifica
ntly
low
erin
the
activ
etre
atm
ent
grou
pve
rsus
the
plac
ebo
grou
p.
100
233
3124
0Y
YY
YY
36Ba
ron-
Bodo
62;
2012
;Fra
nce
Adul
ts18
–50
year
s;St
alle
rgen
esSA
;tot
alpa
tient
s=
509;
imm
unot
hera
py(S
LIT)
;pla
cebo
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Afte
r1ye
arof
SLIT
,mite
-spe
cific
IgE
and
IgG4
titer
sin
crea
sed
by1.
5-fo
ldan
d4-
fold
,re
spec
tivel
y,in
the
activ
e,bu
tno
tin
the
plac
ebo
grou
p.
YY
YY
Y
37W
ahn66
;201
2;Ge
rman
yCh
ildre
n4–
12ye
ars;
Depa
rtmen
tfor
Pedi
atric
Pneu
mol
ogy
and
Imm
unol
ogy;
tota
lpat
ient
s=
93;
stud
y:hi
gh-d
ose
gras
spo
llen
SLIT
=60
;pla
cebo
=23
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
dtri
al
SLIT
prep
arat
ion
sign
ifica
ntly
redu
ced
sym
ptom
san
dm
edic
atio
nus
ein
child
ren
with
gras
spo
llen-
alle
rgic
rhin
ocon
junc
tiviti
s.
3060
723
YY
YY
Y
41Du
rham
94;2
012;
UKAd
ults
18–6
5ye
ars;
Sect
ion
ofAl
lerg
yan
dCl
inic
alIm
mun
olog
y;to
talp
atie
nts=
568;
imm
unot
hera
py=
282;
plac
ebo
=28
6
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
dm
ultin
atio
nal,
phas
eIII
trial
The
mea
nrh
inoc
onju
nctiv
itis
daily
sym
ptom
scor
ew
asre
duce
dby
25%
to36
%(p
�0.
004)
inth
egr
ass
AIT
grou
pco
mpa
red
with
the
plac
ebo
grou
pov
erth
e5
gras
spo
llen
seas
ons
cove
red
byth
etri
al.
177
282
028
6Y
YY
YY
(Co
ntin
ued
)
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 18
Meta-analysis: role of immunotherapy for ARTA
BLE
2.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
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ers
in
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line)
;dat
e;
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tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
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es
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uno
ther
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upP
lace
bo
gro
up
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ruit
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t
of
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ecut
ive
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ient
s
Pat
ient
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om
-
izat
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ilar
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elin
e
char
ac-
teri
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inal
l
gro
ups
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ient
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ded
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lth
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vid
er
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ded
Eq
ual
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to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
43Va
lovi
rta10
6 ;201
1;Fi
nlan
dCh
ildre
n5–
12ye
ars;
Alle
rgy
Clin
ic;t
otal
patie
nts=
812;
imm
unot
hera
py:
gras
sAI
T;pl
aceb
o1:
1ra
ndom
izat
ion
Pros
pect
ive,
mul
tinat
iona
l,do
uble
-blin
d,pl
aceb
o-co
ntro
lled
rand
omiz
edtri
al
Graz
axAs
thm
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even
tion
(GAP
)tri
alto
asse
ssth
epr
even
tive
effe
ctof
alle
rgen
-spe
cific
imm
unot
hera
pyon
asth
ma
deve
lopm
ent.
406
406
040
6Y
YY
YY
44Ku
na10
8 ;201
1;Po
land
Asth
ma
and
Alle
rgy;
tota
lpat
ient
s=
46;
SLIT
;pla
cebo
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
dtri
al
Sym
ptom
san
dm
edic
atio
nin
take
furth
erde
crea
sed
inth
eth
irdye
arof
SLIT
durin
gth
egr
ass
polle
nse
ason
inco
mpa
rison
toth
epr
evio
usye
ars
and
the
num
bero
f“w
ell
days
”in
crea
sed
acco
rdin
gly.
YY
YY
Y
46Re
ich11
9 ;201
1;Ge
rman
yAd
ults
mea
n18
–65y
ears
;De
partm
ento
fDe
rmat
olog
y;to
tal
patie
nts=
276;
imm
unot
hera
py:
gras
sAI
T=
210;
plac
ebo
=52
Pros
pect
ive,
mul
ticen
ter,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
dtri
al
The
chan
gefro
mba
selin
ein
mea
nco
ncen
tratio
nof
IgE-
bloc
king
fact
orw
assi
gnifi
cant
lygr
eate
rwith
gras
sAI
Tco
mpa
red
with
plac
ebo
162
276
1052
YY
YY
Y
47Kl
imek
126 ;2
011;
Germ
any
Adul
ts18
–65
year
s;Ze
ntru
mfu
erRh
inol
ogie
&Al
lerg
olog
ie;t
otal
patie
nts=
299;
imm
unot
hera
py=
202;
plac
ebo
=97
Pros
pect
ive,
doub
le-b
lind,
rand
omiz
ed,
mul
ticen
ter,
phas
eIIb
stud
y
Rhin
ocon
junc
tiviti
ssy
mpt
oms
wer
esi
gnifi
cant
lylo
wer
inpa
tient
stre
ated
with
high
dose
ofCY
T003
-QbG
10as
com
pare
dw
ithpl
aceb
o.Tr
eatm
entw
ithhi
gh-d
ose
CYT0
03-Q
bG10
impr
oved
dise
ase
sym
ptom
san
dre
duce
dm
edic
atio
nus
ein
alle
rgic
indi
vidu
als
thus
prov
idin
gfir
stev
iden
cefo
rane
wpo
tent
ial
imm
unot
hera
peut
ic.
141
202
4897
YY
YY
Y
(Co
ntin
ued
)
19 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.TA
BLE
2.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
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ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
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ilar
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elin
e
char
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teri
stic
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inal
l
gro
ups
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ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
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oth
erth
an
inte
rven
tio
n
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ove
ryTo
tal
Rec
ove
ryTo
tal
48Pa
nzne
r133 ;2
011;
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hRe
publ
icDe
partm
ento
fIm
mun
olog
yan
dAl
lerg
olog
y;to
tal
patie
nts=
51;
imm
unot
hera
py(S
IT,
SLIT
);pl
aceb
o
Pros
pect
ive,
doub
le-b
lind,
plac
ebo-
cont
rolle
d,ra
ndom
ized
The
sign
ifica
ntth
erap
eutic
effe
ctof
both
SLIT
and
supr
alin
gual
imm
unot
hera
pyla
stin
g3
to4
year
sw
ascl
early
achi
eved
.De
spite
nosi
gnifi
cant
diffe
renc
ebe
twee
nef
ficac
yof
both
adm
inis
tratio
nw
ays
ofSI
T,th
eon
seto
fsub
lingu
alSI
Tef
fect
seem
sto
besl
ight
lyfa
ster
than
that
ofsu
pral
ingu
alSI
T.
YY
YY
Y
53Bl
aiss
148 ;2
011;
USA
Child
ren
5–17
year
s;De
partm
ento
fPe
diat
rics;
tota
lpa
tient
s=
345;
imm
unot
hera
py=
175;
plac
ebo
=16
9
Pros
pect
ive,
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le-b
lind,
rand
omiz
ed,
plac
ebo-
cont
rolle
d,pa
ralle
l-gr
oup,
mul
ticen
ter
Use
ofon
ce-d
aily
Tim
othy
gras
sAI
Ttre
atm
ente
ffect
ivel
ytre
ats
timot
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ass
(cro
ss-r
eact
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with
Fest
ucoi
deae
gras
ses)
polle
n-in
duce
dAR
Cin
North
Amer
ican
child
ren
5ye
ars
and
olde
r.
140
175
016
9Y
YY
YY
54M
osge
s150 ;2
010;
Germ
any
Child
ren
6–14
year
s;In
form
atic
san
dEp
idem
iolo
gyDe
pt.;
tota
lpat
ient
s=
54;
imm
unot
hera
py=
27;p
lace
bo=
27
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d,m
ultic
ente
r
The
diffe
renc
ein
mea
nPF
Rch
ange
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ring
ultra
-rus
htit
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nbe
twee
nSL
ITan
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aceb
ow
asno
tsig
nific
ant(
p=
0.05
6).A
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prob
abili
tyth
atSL
ITdo
esno
tdec
reas
ePF
Rdu
ring
ultra
-rus
htit
ratio
nw
asde
mon
stra
ted.
027
027
YY
YY
Y
55Co
rtelli
ni15
2 ;201
0;Ita
lyCh
ildre
nan
dad
ults
14–4
2ye
ars;
Inte
rnal
Med
icin
ean
dRh
eum
atol
ogy
Depa
rtmen
t;to
tal
patie
nts=
26;
imm
unot
hera
py(S
LIT)
and
plac
ebo
Pros
pect
ive,
rand
omiz
ed,
pros
pect
ive,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Afte
rtre
atm
ent,
patie
nts
rece
ivin
gSL
ITha
da
sign
ifica
ntim
prov
emen
tin
sym
ptom
san
da
redu
ctio
nin
med
icat
ion
inta
kevs
plac
ebo
and
vsth
eru
n-in
seas
on,
whe
reas
noch
ange
was
seen
inth
epl
aceb
ogr
oup.
SPT
reac
tivity
sign
ifica
ntly
decr
ease
don
lyin
the
SLIT
grou
p.
YY
YY
Y
(Co
ntin
ued
)
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 20
Meta-analysis: role of immunotherapy for AR
TAB
LE2
.C
ont
inue
d
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
56Pf
aar15
8 ;201
1;Ge
rman
yDe
partm
ento
fOt
orhi
nola
ryng
olog
y;to
talp
atie
nts=
80;
imm
unot
hera
py(S
LIT)
=60
;pla
cebo
=20
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d,ph
ase
I/IIa
stud
y
Patie
nts
inth
e2
grou
psgi
ven
SLIT
cont
aini
ngth
ehi
ghes
tam
ount
ofM
PLex
perie
nced
the
high
estp
ropo
rtion
ofne
gativ
eNC
Tsaf
ter1
0w
eeks
(47%
and
44%
,vs
20%
with
plac
ebo)
.
2860
420
YY
YY
Y
59Ha
lken
173 ;2
010;
Denm
ark
Child
ren
(5–1
1ye
ars)
and
adol
esce
nts
(12–
17ye
ars)
;Han
sCh
ristia
nAn
ders
enCh
ildre
n’s
Hosp
ital;
tota
lpat
ient
s=
267;
imm
unot
hera
py(S
LIT)
;pla
cebo
Pros
pect
ive,
mul
tinat
iona
l,ra
ndom
ized
,do
uble
-blin
d,pl
aceb
o-co
ntro
lled
stud
y
Mor
epa
tient
sin
the
SLIT
grou
pw
ere
satis
fied
with
thei
rtre
atm
entc
ompa
red
topl
aceb
o(8
3.2%
vs68
.1%
,p=
0.00
30),
and
com
plia
nce
was
high
(SLI
T93
.9%
ofpa
tient
sw
ere
com
plia
nt,
plac
ebo
94.8
%of
patie
nts
wer
eco
mpl
iant
).
YY
YY
Y
60Ho
iby17
6 ;201
0;Sw
eden
Child
ren
and
adul
ts7–
69ye
ars;
Depa
rtmen
tof
Resp
irato
ryM
edic
ine
and
Alle
rgol
ogy;
tota
lpa
tient
s=
61;
imm
unot
hera
py(S
CIT)
;pla
cebo
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
dtri
al
SCIT
with
depi
gmen
ted
poly
mer
ized
birc
hpo
llen
extra
ctsi
gnifi
cant
lyre
duce
dsy
mpt
oman
dm
edic
atio
nsc
ores
whe
nco
mpa
red
with
the
plac
ebo,
was
wel
lto
lera
ted,
and
resu
lted
inim
mun
olog
ical
chan
ges
com
para
ble
with
thos
eof
nativ
epo
llen
extra
cts.
YY
YY
Y
62Du
rham
180 ;2
011;
UKAd
ults
34.2
year
s(m
ean)
;Nat
iona
lHe
arta
ndLu
ngIn
stitu
te;t
otal
patie
nts=
634;
imm
unot
hera
py(g
rass
AIT)
=31
6;pl
aceb
o=
318
Pros
pect
ive,
mul
ticen
ter,
doub
le-b
lind,
rand
omiz
ed,
plac
ebo-
cont
rolle
dtri
al
Alld
efini
tions
show
eda
redu
ced
risk
ofha
ving
days
with
seve
resy
mpt
oms
inth
egr
ass
AIT
grou
pw
hen
com
pare
dto
the
plac
ebo
grou
p.
316
316
031
8Y
YY
YY
(Co
ntin
ued
)
21 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.
TAB
LE2
.C
ont
inue
d
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
64Ga
llego
189 ;2
010;
Spai
nRe
sear
chan
dDe
velo
pmen
tDe
partm
ent;
imm
unot
hera
py;
plac
ebo
Pros
pect
ive,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Ther
ew
asa
stat
istic
ally
sign
ifica
ntin
crea
sein
spec
ific
IgG4
,ade
crea
sein
the
ratio
ofIg
E/Ig
G4to
D.pt
eron
yssi
nus
and
asi
gnifi
cant
incr
ease
insp
ecifi
cIg
G4to
Derp
1an
dDe
rp2
inth
epa
tient
sal
lotte
dto
activ
etre
atm
ent.
YY
YY
Y
65Ce
uppe
ns19
3 ;20
09;B
elgi
umDi
visi
onof
Alle
rgy
and
Clin
ical
Imm
unol
ogy;
tota
lpat
ient
s=
62;
imm
unot
hera
py;
plac
ebo
Pros
pect
ive,
mul
ticen
ter,
rand
omiz
ed,
plac
ebo-
cont
rolle
d,do
uble
-blin
d
Trea
tmen
twith
the
birc
hpo
llen
extra
ctre
sulte
din
alo
wer
CIS
fort
heey
ean
dno
sedu
ring
the
peak
birc
hpo
llen
seas
onof
2003
,com
pare
dw
ithpl
aceb
o(re
duct
ions
of42
%an
d31
%,r
espe
ctiv
ely)
(p=
0.01
7an
d0.
039)
.
YY
YY
Y
66Ka
min
200 ;2
010;
Germ
any
Child
ren;
Child
ren’
sHo
spita
l;to
tal
patie
nts=
221;
imm
unot
hera
py;
plac
ebo
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d,m
ultic
ente
r
Tole
rabi
lity
ofSI
Tan
dom
aliz
umab
treat
men
twas
good
(82%
ofpa
tient
s).M
ost
AE(9
3.4%
inom
aliz
umab
and
87.2
%in
plac
ebo
grou
p)w
ere
judg
edby
the
patie
nts
asm
ildto
mod
erat
e.
YY
YY
Y
67O’
Hehi
r201 ;2
009;
Aust
ralia
Adul
ts18
–65
year
s;De
partm
ento
fAlle
rgy,
Imm
unol
ogy
and
Resp
irato
ryM
edic
ine;
tota
lpat
ient
s=
27;
imm
unot
hera
py(H
DMSL
IT)=
13;p
lace
bo=
14
Pros
pect
ive,
rand
omiz
eddo
uble
-blin
dpl
aceb
o-co
ntro
lled
Alle
rgen
-indu
ced
CD4(
+)T-
cell
divi
sion
and
IL-5
prod
uctio
nw
ere
sign
ifica
ntly
decr
ease
daf
ter6
mon
ths
and
12m
onth
sof
activ
etre
atm
entb
utno
tpl
aceb
o.
133
014
YY
YY
Y
(Co
ntin
ued
)
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 22
Meta-analysis: role of immunotherapy for ARTA
BLE
2.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
70Ve
ntur
a208 ;2
009;
Italy
Imm
unol
ogy
and
Infe
ctio
usDi
seas
es;
tota
lpat
ient
s=
40;
imm
unot
hera
py(S
LIT
and
SCIT
);pl
aceb
o
Pros
pect
ive,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Afte
rSCI
Tan
dSL
ITth
ele
vels
ofEC
Pan
dEC
Aw
ere
redu
ced
inna
sall
avag
e.A
clin
ical
impr
ovem
entc
orre
late
dw
itha
decl
ine
inin
flam
mat
ion
para
met
ers
afte
r1ye
arof
imm
unot
hera
py.
YY
YY
71Ts
ai21
6 ;200
9;Ta
iwan
Depa
rtmen
tofE
duca
tion
and
Rese
arch
;tot
alpa
tient
s=
35;
imm
unot
hera
py(L
NIT)
;pla
cebo
Pros
pect
ive,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Whe
nth
esy
mpt
omat
ican
dim
mun
olog
ical
chan
ges
wer
eco
mpa
red
betw
een
activ
etre
atm
enta
ndpl
aceb
ogr
oups
,the
impr
ovem
ents
wer
egr
eate
rin
the
activ
etre
atm
entg
roup
sfo
rall
3sy
mpt
omsc
ores
YY
YY
72M
allin
g218 ;2
009;
Denm
ark
Adul
ts18
–45;
Alle
rgy
Clin
ic;t
otal
patie
nts
=62
8;im
mun
othe
rapy
=44
7;pl
aceb
o=
181
Pros
pect
ive,
mul
tinat
iona
l,ra
ndom
ized
,do
uble
-blin
d,pl
aceb
o-co
ntro
lled
The
risk-
bene
fitra
tiova
lidat
esth
eus
eof
300
IRta
blet
sin
clin
ical
prac
tice
inal
loft
hese
patie
ntsu
bgro
ups,
rega
rdle
ssof
seve
rity
profi
le,
sens
itiza
tion
stat
us,a
ndpr
esen
ceof
asth
ma.
447
447
018
1Y
YY
YY
73Ts
eng22
5 ;200
8;Ta
iwan
Child
ren
6–18
year
s;De
partm
ento
fPe
diat
rics;
tota
lpa
tient
s=
59;
imm
unot
hera
pySL
IT=
28;p
lace
bo=
31
Pros
pect
ive,
mul
ticen
ter,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Spec
ific
IgE
incr
ease
dsi
gnifi
cant
lyin
both
plac
ebo
and
SLIT
grou
psaf
ter
treat
men
tbut
did
notd
iffer
betw
een
the
2gr
oups
.
2828
3131
YY
YY
Y
74W
ahn22
6 ;200
9;Ge
rman
yCh
ildre
n5–
17ye
ars;
Berli
nCh
ildre
n’s
Hosp
ital;
tota
lpa
tient
s=
266;
imm
unot
hera
pySL
IT=
131;
plac
ebo
=13
5
Pros
pect
ive,
mul
tinat
iona
l,ra
ndom
ized
,do
uble
-blin
d,pl
aceb
o-co
ntro
lled
Five
-gra
ss-p
olle
nSL
ITta
blet
s(3
00IR
)red
uce
both
sym
ptom
scor
esan
dre
scue
med
icat
ion
use
inch
ildre
nan
dad
oles
cent
sw
ithgr
ass
polle
n-re
late
drh
inoc
onju
nctiv
itis.
8513
167
135
YY
YY
Y
(Co
ntin
ued
)
23 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.TA
BLE
2.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
76Ro
der23
9 ;200
8;Th
eNe
ther
land
sCh
ildre
n6–
18;S
ectio
nof
Alle
rgol
ogy;
tota
lpa
tient
s=
154;
imm
unot
hera
py(S
LIT)
;pla
cebo
Pros
pect
ive,
rand
omiz
ed,
plac
ebo-
cont
rolle
d
Sym
ptom
scor
esdi
dno
tdiff
erbe
twee
nad
here
ntan
dno
nadh
eren
tpar
ticip
ants
.In
adhe
rent
asw
ella
sno
nadh
eren
tpar
ticip
ants
,no
diffe
renc
ew
asfo
und
betw
een
veru
man
dpl
aceb
ogr
oup
with
resp
ectt
osy
mpt
omsc
ores
.
YY
Y
78Pu
rohi
t246 ;2
008;
Fran
ceSe
rvic
ede
Pneu
mol
ogie
;to
talp
atie
nts=
124;
imm
unot
hera
py;
plac
ebo
Pros
pect
ive,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Sing
leco
urse
sof
inje
ctio
nim
mun
othe
rapy
with
Betv
1al
lerg
ende
rivat
ives
show
edtre
nds
tow
ard
impr
oved
wel
l-bei
ngan
dre
duce
dre
activ
ityto
spec
ific
alle
rgen
prov
ocat
ion
YY
YY
81Pf
aar25
5 ;200
8;Ge
rman
yRh
inol
ogy
and
Alle
rgol
ogy
Cent
er;
tota
lpat
ient
=18
5;im
mun
othe
rapy
SLIT
;pl
aceb
o
Pros
pect
ive,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Activ
etre
atm
entw
asas
soci
ated
with
asi
gnifi
cant
and
clin
ical
lyre
leva
ntim
prov
emen
t.Hi
gh-d
ose,
subl
ingu
al,
spec
ific
imm
unot
hera
pyw
ithan
extra
ctof
a6-
gras
spo
llen
mix
ture
show
eda
sign
ifica
ntan
dcl
inic
ally
rele
vant
impr
ovem
enti
nsu
bjec
tsw
ithgr
ass
polle
n-as
soci
ated
rhin
itis
orrh
inoc
onju
nctiv
itis,
with
orw
ithou
tast
hma.
YY
YY
85Di
dier
273 ;2
007;
Fran
ceAd
ults
18–4
5ye
ars;
Depa
rtmen
tof
Pneu
mol
ogy;
tota
lpa
tient
s=
628;
imm
unot
hera
py(S
LIT)
=47
2;pl
aceb
o=
156
Pros
pect
ive,
mul
tinat
iona
l,ra
ndom
ized
,do
uble
-blin
d,pl
aceb
o-co
ntro
lled
Inth
efir
stpo
llen
seas
on,t
heef
ficac
yan
dsa
fety
ofsu
blin
gual
imm
unot
hera
pyw
ithgr
ass
tabl
ets
was
confi
rmed
.The
300-
IRan
d50
0-IR
dose
sbo
thde
mon
stra
ted
sign
ifica
ntef
ficac
yco
mpa
red
with
plac
ebo.
472
472
015
6Y
YY
YY
(Co
ntin
ued
)
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 24
Meta-analysis: role of immunotherapy for AR
TAB
LE2
.C
ont
inue
d
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
86Sr
ivas
tava
274 ;
2007
;Ind
iaAl
lerg
yan
dIm
mun
olog
ySe
ctio
ns;t
otal
patie
nts=
40;
imm
unot
hera
py;
plac
ebo
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Alle
rgen
imm
unot
hera
pyw
ithm
osqu
itoex
tract
was
wel
lto
lera
ted,
with
impr
ovem
ent
insy
mpt
oms
and
airw
ayre
activ
ity.G
ood
clin
ical
outc
ome
was
asso
ciat
edw
ithin
crea
sed
IgG4
antib
ody
leve
ls.
YY
YY
Y
87Po
wel
l277 ;2
007;
UKAd
ults
37–3
8ye
ars;
Clin
ical
Imm
unol
ogy
Unit;
tota
lpat
ient
s=
410;
imm
unot
hera
py=
307;
plac
ebo
=10
3
Pros
pect
ive,
doub
le-b
lind,
rand
omiz
ed,
plac
ebo-
cont
rolle
d
Trea
tmen
twith
Alut
ard
SQsi
gnifi
cant
lyim
prov
edth
ese
ason
alQo
Lof
patie
nts
suffe
ring
from
alle
rgic
rhin
ocon
junc
tiviti
s.
307
307
010
3Y
YY
YY
88Ko
pp27
8 ;200
7;Ge
rman
yCh
ildre
nan
dad
oles
cent
s(6
.3–1
7.6
year
s;Un
iver
sity
Child
ren’
sHo
spita
l;to
tal
patie
nts=
170;
imm
unot
hera
py;
plac
ebo
Pros
pect
ive,
phas
eIII
,ra
ndom
ized
,pl
aceb
o-co
ntro
lled,
mul
ticen
ter
One
year
afte
rom
aliz
umab
orpl
aceb
otre
atm
ent,
ther
ew
asno
sign
ifica
ntdi
ffere
nce
inSL
Tre
leas
ebe
twee
nth
e4
grou
ps.
Thes
ere
sults
stro
ngly
sugg
est
that
the
obse
rved
effe
cts
ofde
crea
sed
SLT
rele
ase
afte
rom
aliz
umab
treat
men
twer
eat
tribu
tabl
eto
the
treat
men
tw
ithom
aliz
umab
,rat
hert
han
toSI
Tth
erap
y.
YY
Y
89Ib
anez
279 ;2
007;
Spai
nCh
ildre
n5–
12ye
ars;
Serv
icio
deAl
ergi
a;to
talp
atie
nts=
60;
imm
unot
hera
py(S
LIT)
;pla
cebo
Pros
pect
ive,
rand
omiz
ed,
plac
ebo-
cont
rolle
d
Graz
axw
asin
gene
ralt
oler
ated
ina
pedi
atric
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latio
nan
dco
nsid
ered
suita
ble
forf
urth
ercl
inic
alin
vest
igat
ions
inch
ildre
n
YY
Y
(Co
ntin
ued
)
25 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.TA
BLE
2.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
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tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
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ive
pat
ient
s
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ient
rand
om
-
izat
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ilar
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elin
e
char
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teri
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inal
l
gro
ups
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ient
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Hea
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care
pro
vid
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Eq
ual
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pat
ient
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oth
erth
an
inte
rven
tio
n
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ove
ryTo
tal
Rec
ove
ryTo
tal
90Kl
unke
r281 ;2
007;
UKAd
ults
21–5
1ye
ars;
Sect
ion
ofAl
lerg
yan
dCl
inic
alIm
mun
olog
y;to
talp
atie
nts=
36;
imm
unot
hera
py=
27;p
lace
bo=
9
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
The
com
bina
tion
ofra
gwee
dim
mun
othe
rapy
and
anti-
IgE
resu
lted
inpr
olon
ged
inhi
bitio
nof
alle
rgen
-IgE
bind
ing
com
pare
dw
ithei
ther
treat
men
talo
ne,e
vent
sth
atm
ight
cont
ribut
eto
enha
nced
effic
acy.
2727
09
YY
YY
Y
91Ca
lder
on28
2 ;200
7;UK
Adul
ts18
–65;
Natio
nal
Hear
tand
Lung
Inst
itute
;tot
alpa
tient
s=
934;
imm
unot
hera
py(S
LIT)
=48
0;pl
aceb
o=
454
Pros
pect
ive,
rand
omiz
ed,
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le-b
lind,
plac
ebo-
cont
rolle
d,m
ultic
ente
r
Subl
ingu
alim
mun
othe
rapy
with
Graz
ax)m
ustb
ein
itiat
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leas
t8w
eeks
prio
rto
the
gras
spo
llen
seas
onto
prov
ide
asi
gnifi
cant
clin
ical
effic
acy.
Alo
nger
pres
easo
nalt
reat
men
tpe
riod
(>8
wee
ks)i
mpr
oves
the
clin
ical
effic
acy
(rela
tive
topl
aceb
o)du
ring
the
gras
spo
llen
seas
on.
480
480
454
454
YY
YY
Y
94W
illia
ms28
9 ;200
7;UK
Hom
erto
nUn
iver
sity
Hosp
ital;
tota
lpa
tient
s=
154;
imm
unot
hera
py(S
IT);
plac
ebo
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
mul
ticen
ter,
plac
ebo-
cont
rolle
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Pres
easo
nals
hort-
term
imm
unot
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ithth
ehi
gh-d
ose,
hypo
alle
rgen
ical
lerg
enpr
epar
atio
nAl
lerg
ovit
has
been
show
nto
beef
ficac
ious
and
safe
.
YY
YY
Y
95W
orm
304 ;2
007;
Germ
any
Klin
ikfu
rDer
mat
olog
ieun
dAl
lerg
olog
ie;t
otal
patie
nts;
imm
unot
hera
py(S
CIT)
;pla
cebo
Pros
pect
ive,
mul
ticen
ter,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Diffe
renc
eof
46%
inm
ean
sym
ptom
med
icat
ion
scor
ebe
twee
nac
tive
and
plac
ebo
grou
pw
asse
en.H
igh
dose
subl
ingu
alim
mun
othe
rapy
can
ther
efor
ebe
cons
ider
edas
anef
ficie
ntth
erap
eutic
optio
nin
the
man
agem
ento
fIg
E-m
edia
ted
alle
rgic
airw
aydi
seas
es.
YY
YY
Y
(Co
ntin
ued
)
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 26
Meta-analysis: role of immunotherapy for ARTA
BLE
2.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
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ecut
ive
pat
ient
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ient
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om
-
izat
ion
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ilar
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elin
e
char
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teri
stic
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inal
l
gro
ups
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ient
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ded
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lth
care
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vid
er
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ded
Eq
ual
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to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
98Ve
rvlo
et31
1 ;200
7;Fr
ance
Serv
ice
dePn
eum
olog
ie;
tota
lpat
ient
s=
74;
imm
unot
hera
py(S
LIT)
;pla
cebo
Pros
pect
ive,
doub
le-b
lind
plac
ebo-
cont
rolle
d
Ther
ew
asa
mar
ked
and
sign
ifica
ntde
crea
seof
the
med
icat
ion
scor
e(a
bout
50%
)an
dna
sals
tero
idco
nsum
ptio
n(a
bout
75%
)in
the
activ
etre
atm
entg
roup
.
YY
YY
99Pa
lma-
Carlo
s314 ;
2006
;Por
tuga
lAd
ults
19–4
3ye
ars;
Clin
ical
Alle
rgy
Imm
unol
ogy;
tota
lpa
tient
s=
32;
imm
unot
hera
py(S
LIT)
;pla
cebo
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
The
resu
ltsof
this
stud
ysh
owth
atth
eal
lerg
oid
SLIT
issa
fean
def
fect
ive
inde
crea
sing
sym
ptom
scor
esan
ddr
ugus
ein
rhin
itic
patie
nts
alle
rgic
togr
ass
polle
n.
YY
YY
Y
104
Dahl
326 ;2
006;
Denm
ark
Adul
ts18
–65
year
s;De
partm
ento
fRe
spira
tory
Dise
ases
;to
talp
atie
nts=
634;
imm
unot
hera
py(S
LIT)
=31
6;pl
aceb
o=
318
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d,m
ultic
ente
r
SLIT
with
gras
sal
lerg
enta
blet
sw
asef
fect
ive
ingr
ass
polle
n-in
duce
drh
inoc
onju
nctiv
itis.
120
316
031
8Y
YY
YY
109
Doki
c358 ;2
005;
Repu
blic
ofM
aced
onia
Clin
icof
Pulm
onol
ogy
and
Alle
rgol
ogy;
tota
lpa
tient
s=
40;
imm
unot
hera
py(S
IT)
=20
;pla
cebo
=20
Pros
pect
ive,
doub
le-b
lind,
rand
omiz
ed,
plac
ebo-
cont
rolle
d
Spec
ific
imm
unot
hera
pyw
itha
mite
depo
talle
rgoi
din
duce
dsi
gnifi
cant
clin
ical
impr
ovem
ents
vspl
aceb
o.
2020
020
YY
YY
Y
110
Mar
cucc
i369 ;
2005
;Ita
lyCh
ildre
n4–
16ye
ars;
Clin
ica
Pedi
atric
a;to
talp
atie
nts=
24;
imm
unot
hera
py(S
LIT)
=13
;pla
cebo
=11
Pros
pect
ive,
doub
le-b
lind,
rand
omiz
ed,
plac
ebo-
cont
rolle
d
SLIT
inch
ildre
nm
onos
ensi
tized
tom
ites
reve
rted
the
spon
tane
ous
incr
ease
inna
sal
IgE
and
inlo
calp
aram
eter
sof
alle
rgic
infla
mm
atio
n.
Y13
130
11Y
YY
YY
115
Bodt
ger39
2 ;200
5;De
nmar
kAd
ults
19–4
5ye
ars;
Alle
rgy
Clin
ic;t
otal
patie
nts=
35;
imm
unot
hera
py;
plac
ebo
Retro
spec
tive,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Desp
itebe
ing
com
para
ble
pret
reat
men
t,on
lyth
eSI
Tgr
oup
had
asi
gnifi
cant
decr
ease
inre
colle
cted
tota
ldr
ugus
edu
ring
SIT.
YY
YY
(Co
ntin
ued
)
27 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.TA
BLE
2.
Co
ntin
ued
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
Sim
ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
116
Bow
en40
2 ;200
4;Ca
nada
Child
ren
and
adul
ts;
Depa
rtmen
tof
Med
icin
ean
dPe
diat
rics;
tota
lpa
tient
s=
76;
imm
unot
hera
py;
plac
ebo
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind
plac
ebo-
cont
rolle
d
Subl
ingu
alsw
allo
wim
mun
othe
rapy
seem
sto
besa
fean
def
ficac
ious
for
ragw
eed
rhin
ocon
junc
tiviti
sev
enw
hen
star
ted
imm
edia
tely
befo
reth
era
gwee
dpo
llen
seas
on.
YY
YY
Y
117
Rolin
ck-
Wer
ning
haus
404 ;
2004
;Ger
man
y
Child
ren
3–14
year
s;De
partm
ento
fPe
diat
ricPn
eum
olog
yan
dIm
mun
olog
y;to
talp
atie
nts=
97;
imm
unot
hera
py=
49;p
lace
bo=
48
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind
plac
ebo-
cont
rolle
d,m
ultic
ente
r
SLIT
had
apo
sitiv
eef
fect
onth
ere
duct
ion
ofa
mul
tiple
sym
ptom
-med
icat
ion
scor
e,bu
thad
nosi
gnifi
cant
effe
cton
sym
ptom
sal
one
inch
ildre
nw
ithrh
inoc
onju
nctiv
itis
togr
ass
polle
nco
mpa
red
with
apl
aceb
o.
2749
448
YY
YY
Y
118
Smith
406 ;2
004;
UKAd
ults
18–6
0ye
ars;
Wes
sex
Rese
arch
Netw
ork;
tota
lpa
tient
s=
140;
imm
unot
hera
py=
94;p
lace
bo=
46
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
High
-dos
eSL
ITha
sbe
nefic
ial
effe
cts
onna
sals
ympt
oms
durin
gth
epe
akpo
llen
seas
onin
patie
nts
with
seve
rese
ason
alal
lerg
icrh
initi
s.At
leas
t2ye
ars
oftre
atm
entw
ithSL
ITis
requ
ired
tosh
owa
bene
fit.
5294
2346
YY
YY
Y
121
Bez41
7 ;200
4;Ge
rman
yCh
ildre
n6–
17ye
ars;
Univ
ersi
tyCh
ildre
n’s
Hosp
ital;
tota
lpa
tient
s=
201;
imm
unot
hera
py=
111;
plac
ebo
=90
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
The
com
bina
tion
ofSI
Tan
dan
ti-Ig
Eis
asso
ciat
edw
ithpr
even
tion
ofna
salE
CPin
crea
sean
dde
crea
sed
tryp
tase
leve
lsin
nasa
lse
cret
ions
.
111
111
090
YY
YY
Y
129
Asci
one44
2 ;200
3;Ita
lyEN
TIn
stitu
te;t
otal
patie
nts;
imm
unot
hera
py(L
NIT)
;pla
cebo
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
Com
pare
dto
plac
ebo
the
clin
ical
effic
acy
ofLN
ITw
asco
nfirm
edby
are
duct
ion
ofcl
inic
alsy
mpt
oms
and
drug
inta
ke.
YY
YY
Y
(Co
ntin
ued
)
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 28
Meta-analysis: role of immunotherapy for AR
TAB
LE2
.C
ont
inue
d
Stud
ynu
mb
er
inth
ere
fere
nce
list
of
the
met
a-an
alys
is
(thi
sar
ticl
e)a
Aut
hor
(stu
dy
num
ber
into
talo
f
464
pap
ers
in
Med
line)
;dat
e;
coun
tryb
Po
pul
atio
nSt
udy
typ
e/
blin
din
g
Out
com
es
Imm
uno
ther
apy
gro
upP
lace
bo
gro
up
Rec
ruit
men
t
of
cons
ecut
ive
pat
ient
s
Pat
ient
rand
om
-
izat
ion
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ilar
bas
elin
e
char
ac-
teri
stic
s
inal
l
gro
ups
Pat
ient
blin
ded
Hea
lth
care
pro
vid
er
blin
ded
Eq
ual
trea
tmen
to
f
pat
ient
s
oth
erth
an
inte
rven
tio
n
Rec
ove
ryTo
tal
Rec
ove
ryTo
tal
130
Varn
ey44
6 ;200
3;UK
Adul
ts19
–55;
RCM
BRe
sear
chDi
visi
on;
tota
lpat
ient
s=
28;
imm
unot
hera
py=
15;p
lace
bo=
13
Pros
pect
ive,
rand
omiz
ed,
doub
le-b
lind,
plac
ebo-
cont
rolle
d
One
year
ofSI
Tfo
rD.
pter
onys
sinu
sin
patie
nts
with
poor
lyco
ntro
lled
rhin
itis
(+/−
mild
asth
ma)
prod
uced
clin
ical
lyus
eful
impr
ovem
ent
assh
own
bysy
mpt
om-m
edic
atio
ndi
ary
card
san
dre
duct
ions
inim
med
iate
skin
reac
tions
com
pare
dw
ithpl
aceb
otre
atm
ent.
1515
013
YY
YY
Y
131
Radc
liffe
448 ;2
003;
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29 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.
TABLE 3. Meta analysis studies on effects of ımmunotherapy and placebo in the recoverement of allergic rhinitis
133 457 Andre et al., 2003 43 43 0 49 98.86 6.27 1559.06 1.42
aThe numbers of studies in this column reflect study numbers in the reference list of this meta-analysis. All 56 studies were clinical and placebo-controlled; and exhibiteda homogeneous distribution.bThe numbers of the studies refer to a total of 464 papers in Medline detected by searching with the key phrase “allergic rhinitis and immunotherapy and clinical study”;all papers were published between 2013 and 2003.CI = confidence interval; RR = risk ratio.
SCIT to treat of seasonal AR4 showed that the approachwas efficacious, as revealed by reductions in seasonal symp-toms and the need for rescue medication, compared withplacebo. SLIT involves the regular self-administration andretention of allergen extract under the tongue for 1 to 2minutes before the extract is swallowed. Recent systematicreviews with meta-analyses have demonstrated the efficacyof SLIT in children.91,145 It is not yet clear from these stud-ies whether SCIT and SLIT are of equivalent efficacy.
The aim of the present study was to conduct a meta-analysis on the effectiveness of allergen immunotherapy.A total of 56 homogeneous studies were included inthe analysis. The inclusion criteria used to select articleswere: (1) placebo-controlled clinical trials; (2) the use of
immunotherapy; (3) participants and/or physicians were orwere not blinded to immunotherapy or placebo assignment(single-blinding, double-blinding, or no-blinding studies);and (4) randomization or not of those in the immunother-apy and placebo groups.
Between 2003 and 2013, 114 placebo-controlled clinicaltrials were reported in Medline. Studies describing recov-ery rates in immunotherapy and placebo groups numbered56. The distribution of such works was homogeneous (het-erogeneity chi-squared = 16.11; df = 55; p = 1.000). Theresults of our meta-analysis suggest that the extent of recov-ery in the immunotherapy group was 53.671-fold greaterthan in the placebo group (M-H pooled RR = 53.671; 95%CI, 36.981 to 77.893; z = 20.96; p < 0.001).
31 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.
FIGURE 2. Forest plot. The central square on each horizontal line represents the RR for each study. The lines delimit the 95% CI intervals. The vertical line atan RR of 1 is the line of no effect. The [%weight] values indicate the influence exerted by each study on the pooled RR. The results of 56 studies are summarizedin this figure. The reference numbers of the studies refer to a total of 464 papers in Medline detected by searching with the key phrase “allergic rhinitis andimmunotherapy and clinical study”; all papers were published between 2003 and 2013. The meta-analysis numbers of the studies appear in Tables 1 and 2. All56 studies were clinical and placebo-controlled; and exhibited a homogeneous distribution. RR = risk ratio; CI = confidence interval.
International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 32
Meta-analysis: role of immunotherapy for AR
FIGURE 3. Funnel plot. The vertical solid line represents the logarithmictransformation of the overall estimated treatment effect (ie, the log [RR]).Diagonal dotted lines represent pseudo-95% confidence limits for estimatedtreatment effects, and the circles show the treatment effects of each of the56 studies. The results of 56 studies are shown in this figure. The referencenumbers of the studies refer to a total of 464 papers in Medline detectedby searching with the key phrase “allergic rhinitis and immunotherapy andclinical study”; all papers were published between 2013 and 2003. The meta-analysis numbers of the studies appear in Tables 1 and 2. All 56 studies wereclinical and placebo-controlled; and exhibited a homogeneous distribution.In the immunotherapy arms of the 56 studies, the mean number of thepatients was 76.4 (minimum 7.0, maximum 705.0). RR = risk ratio.
When immunotherapy was applied, shortly after initia-tion of immunotherapy, an increase in the level of CD41-CD251 regulatory T lymphocytes secreting interleukin-10 (IL-10) and transforming growth factor β (TGF-β)is evident, associated with immunological tolerance, de-fined as a long-lived decrease in allergen-specific T-cellresponsiveness.82,137–141 Upon continued immunotherapy,the response wanes to some extent, and immune devia-tion from a T helper 2 (TH2) to a T helper 1 (TH1) cy-tokine response to the administered allergen comes intoplay (A).136 Specific IgE levels initially increase and thengradually decrease. The levels of specific IgG1, IgG4, andIgA increase.82,137–141
Many controlled studies have shown that both SCITand SLIT improve asthma symptoms in atopic asthmaticadults and children clinically sensitized to seasonal andperennial allergens.146–148 Meta-analyses149–151 of placebo-controlled trials in asthma patients suggest that small butsignificant improvements in symptoms and lung functiondevelop upon active therapy, compared with placebo.
After 3 to 4 years of SCIT, no significant change in ei-ther symptom or medication score was evident during thesubsequent 3 pollen seasons.152 The data suggest that 3years of grass pollen SCIT affords benefits that persist fora further 3 years after discontinuation, whereas any poten-tial long-term benefit after discontinuation of SCIT usingperennial allergens remains to be determined. SLIT mayalso have long-term effects. A double-blind, randomized,controlled trial of grass allergen tablet immunotherapy inadults with moderate/severe persistent seasonal AR showed
that 3 years of treatment resulted in an approximately 30%reduction in symptoms and a 40% decrease in the use ofantiallergic drugs; these reductions were maintained for 1year after treatment cessation. A disease-modifying effectwas also evident.153
SLIT is safer than SCIT, although severe 155reactionsmay occur rarely.154,155 SLIT is administered at home andpatients should be educated on how to recognize andtreat a reaction if it occurs. It is also important to ex-plore the time course of severe reactions developing afterimmunotherapy.155 SCIT is also safe when performed onselected individuals, in a specialist clinic with adequate fa-cilities, by trained healthcare professionals. Patients treatedwith SCIT are at risk of both local and systemic adversereactions but, in the vast majority of cases, the symp-toms are readily reversible if they are recognized early andtreated promptly. Some physicians may request that thoseconsidered at increased risk of serious systemic reactionsoutside of the office/medical clinic should carry injectableepinephrine.155–162
Because our results suggested that recovery in the im-munotherapy group was greater than the placebo group,we recommend to use immunotherapy when needed. BothSCIT or SLIT are safe when performed on selected individ-uals.
ConclusionOur meta-analysis showed that the extent of recovery inimmunotherapy patients was 53.671-fold greater than thatin placebo patients (M-H pooled RR = 53.671; 95% CI,36.981 to 77.893; z = 20.96; p < 0.001).
AcknowledgmentsPreparation of this article, including design and planning,was supported by the Continuous Education and ScientificResearch Association.
Appendix 1: Classification ofrecommendations and evidence136
Category of evidenceIa. Evidence from meta-analysis of randomized con-
trolled trials.Ib. Evidence from at least 1 randomized controlled trial.IIa. Evidence from at least 1 controlled study without ran-
domization.IIb. Evidence from at least 1 other type of quasi-
experimental study.III. Evidence from non-experimental descriptive studies,
such as comparative studies.IV. Evidence from expert committee reports or opinions
or clinical experience of respected authorities, or both.LB. Evidence from laboratory-based studies.
NR. Not rated.
33 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014
Cingi et al.
Strength of recommendationA. Directly based on category I evidence.B. Directly based on category II evidence or extrapolated
recommendation from category I evidence.C. Directly based on category III evidence or extrapolated
recommendation from category I or II evidence.D. Directly based on category IV evidence or extrapolated
recommendation from category I, II, or III evidence.
Appendix 2: Revised grading system forrecommendations in evidence-based
guidelines
Levels of evidence1++. High-quality meta-analyses, systematic reviews of
randomized controlled trials (RCTs), or RCTs with a verylow risk of bias.
1+. Well-conducted meta-analyses, systematic reviews ofRCTs, or RCTs with a low risk of bias.
Meta-analyses, systematic reviews or RCTs, or RCTs witha high risk of bias.
2++. High quality systematic reviews of case-control or co-hort studies or High quality case-control or cohort studieswith a very low risk of confounding, bias, or chance anda high probability that the relationship is causal.
2+. Well conducted case-control or cohort studies with alow risk of confounding, bias, or chance and a moderateprobability that the relationship is causal.
2. Case-control or cohort studies with a high risk of con-founding, bias, or chance and a significant risk that therelationship is not causal.
3. Non-analytic studies, eg case reports, case series.4. Expert opinion.
Grades of recommendationsA. At least 1 meta-analysis, systematic review, or RCT
rated as 1++ and directly applicable to the target pop-ulation or A systematic review of RCTs or a body ofevidence consisting principally of studies rated as 1+directly applicable to the target population and demon-strating overall consistency of results.
B. A body of evidence including studies rated as 2++ di-rectly applicable to the target population and demon-strating overall consistency of results or Extrapolatedevidence from studies rated as 1++ or 1+.
C. A body of evidence including studies rated as 2+ di-rectly applicable to the target population and demon-strating overall consistency of results or Extrapolatedevidence from studies rated as 2++.
D. Evidence level 3 or 4 or Extrapolated evidence fromstudies rated as 2+.
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