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).

Conclusion: Our meta-analysis suggests that immunother-apy is associated with a recovery rate 53.671-fold that ofplacebo. 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, 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:nbayarmuluk@yahoo.com; nurayb@hotmail.com

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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Meta-analysis: role of immunotherapy for ARTA

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5 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014

Cingi et al.TA

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International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 6

Meta-analysis: role of immunotherapy for ARTA

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7 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014

Cingi et al.TA

BLE

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International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 8

Meta-analysis: role of immunotherapy for AR

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9 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014

Cingi et al.TA

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1414

011

YY

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International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014 10

Meta-analysis: role of immunotherapy for AR

TAB

LE1

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ont

inue

d

Stud

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mb

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ere

fere

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)

11 International Forum of Allergy & Rhinology, Vol. 00, No. 00, November 2014

Cingi et al.

TAB

LE1

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ont

inue

d

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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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

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py=

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lace

bo=

79

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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

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hor

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dy

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f

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e;

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lace

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om

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123

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el42

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ance

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ren

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adul

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This

stud

yin

dica

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the

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riorit

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etre

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vspl

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o,ev

alua

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onef

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(rhin

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obje

ctiv

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(ski

nre

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1515

017

YY

Y

124

van

Neer

ven42

4 ;20

04;D

enm

ark

ALK-

Abel

loto

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nts

=42

;im

mun

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rapy

=21

;pla

cebo

=21

Pros

pect

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plac

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Spec

ific

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Pne

eded

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tain

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cell

activ

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YY

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125

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s428 ;2

004;

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year

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visi

onof

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unol

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and

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rtmen

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s;to

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patie

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imm

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lace

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pect

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rand

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alle

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and

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safe

,ef

ficie

nt,a

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met

hod

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lerg

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mun

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rapy

.

1212

011

YY

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126

Khin

chi43

2 ;200

4;De

nmar

kAd

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patie

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58;

imm

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LIT,

SCIT

)=39

;pla

cebo

=19

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pect

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lind,

plac

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rolle

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Base

don

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nts

the

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ical

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rent

from

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,and

both

treat

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inic

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ctiv

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with

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etre

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3939

019

YY

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127

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o435 ;2

003;

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edia

tric

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=15

;pla

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=15

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d

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ical

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ofSL

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ptom

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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

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hor

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dy

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e;

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ncSt

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e/

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din

g

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com

es

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uno

ther

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gro

upP

lace

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up

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ruit

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of

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ive

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ient

s

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ient

rand

om

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ion

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elin

e

char

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stic

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ded

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vid

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ded

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rven

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n

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ryTo

tal

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ove

ryTo

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128

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hric

h437 ;2

003;

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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

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with

agr

ass

polle

nex

tract

isw

ellt

oler

ated

inch

ildre

nan

dis

able

tosi

gnifi

cant

lyre

duce

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cons

umpt

ion

durin

gth

ese

cond

year

oftre

atm

ent.

1010

010

YY

YY

132

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sa45

1 ;200

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lyAd

ults

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ars;

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rtim

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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,

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le-b

lind,

plac

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rolle

d

The

clin

ical

effic

acy

ofPa

rieta

riaSI

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asex

clus

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ated

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nuat

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inse

ason

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orse

ning

ofPC

15AM

P,su

gges

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eful

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onito

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inal

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mat

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1515

015

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133

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e457 ;2

003;

Fran

ceDe

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ical

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lace

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pect

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ed,

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le-b

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Durin

gth

ew

hole

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dof

polli

natio

n,th

edi

ffere

nce

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ring

imm

unot

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pyw

ashi

ghly

sign

ifica

ntfo

rthe

glob

alas

sess

men

tby

the

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nt(p

=0.

004)

and

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vest

igat

or(p

=0.

005)

.Ad

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nsw

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repo

rted

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eof

ten

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and

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stm

ent.

4343

049

YY

YY

Y

aTh

enu

mb

ers

of

stud

ies

inth

isco

lum

nar

eth

est

udy

num

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sin

the

refe

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elis

to

fth

ism

eta-

anal

ysis

.All

56st

udie

sw

ere

clin

ical

and

pla

ceb

o-c

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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.

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eo

ther

pap

ers,

the

used

typ

eo

fth

eim

mun

oth

erap

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asre

po

rted

asim

mun

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erap

yo

rSI

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Ad

SS=

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rag

eA

dju

sted

Sym

pto

mSc

ore

;A

E=

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rse

even

t;A

IC=

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ba

1-im

mun

ost

imul

ato

ryp

hosp

horo

thio

ate

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onu

cleo

tid

eco

njug

ate;

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=al

lerg

yim

mun

oth

erap

yta

ble

t;A

MP

=Ad

eno

sine

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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

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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

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acte

rial

extr

acts

;DR

F=

do

sera

nge-

find

ing

;FA

P=F

acili

tate

dA

llerg

enP

rese

ntat

ion;

GIN

A=

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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

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edic

atio

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ore

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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

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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

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

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

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

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

aPr

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

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

48Pa

nzne

r133 ;2

011;

Czec

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,

doub

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

hygr

ass

(cro

ss-r

eact

ive

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

sdu

ring

ultra

-rus

htit

ratio

nbe

twee

nSL

ITan

dpl

aceb

ow

asno

tsig

nific

ant(

p=

0.05

6).A

95%

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,

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le-b

lind,

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omiz

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plac

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rolle

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al

Alld

efini

tions

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eda

redu

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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

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(stu

dy

num

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into

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e;

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up

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of

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ive

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ient

s

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ient

rand

om

-

izat

ion

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elin

e

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s

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64Ga

llego

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chan

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velo

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partm

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imm

unot

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py;

plac

ebo

Pros

pect

ive,

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cont

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d

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ew

asa

stat

istic

ally

sign

ifica

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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

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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’

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009;

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ralia

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ts18

–65

year

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partm

ento

fAlle

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unol

ogy

and

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edic

ine;

tota

lpat

ient

s=

27;

imm

unot

hera

py(H

DMSL

IT)=

13;p

lace

bo=

14

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pect

ive,

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omiz

eddo

uble

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dpl

aceb

o-co

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lled

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rgen

-indu

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CD4(

+)T-

cell

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sion

and

IL-5

prod

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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

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line)

;dat

e;

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tryb

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e/

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din

g

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com

es

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uno

ther

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gro

upP

lace

bo

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up

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ruit

men

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of

cons

ecut

ive

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ient

s

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ient

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om

-

izat

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elin

e

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70Ve

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lpat

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unot

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py(S

LIT

and

SCIT

);pl

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o

Pros

pect

ive,

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plac

ebo-

cont

rolle

d

Afte

rSCI

Tan

dSL

ITth

ele

vels

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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,

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le-b

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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

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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,

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ticen

ter,

rand

omiz

ed,

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le-b

lind,

plac

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cont

rolle

d

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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

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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

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line)

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e;

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nSt

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e/

blin

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g

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com

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uno

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upP

lace

bo

gro

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of

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ient

s

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om

-

izat

ion

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elin

e

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ac-

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rven

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76Ro

der23

9 ;200

8;Th

eNe

ther

land

sCh

ildre

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18;S

ectio

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rgol

ogy;

tota

lpa

tient

s=

154;

imm

unot

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py(S

LIT)

;pla

cebo

Pros

pect

ive,

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omiz

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ebo-

cont

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d

Sym

ptom

scor

esdi

dno

tdiff

erbe

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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

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py;

plac

ebo

Pros

pect

ive,

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le-b

lind,

plac

ebo-

cont

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d

Sing

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urse

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inje

ctio

nim

mun

othe

rapy

with

Betv

1al

lerg

ende

rivat

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show

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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

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rapy

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;pl

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o

Pros

pect

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le-b

lind,

plac

ebo-

cont

rolle

d

Activ

etre

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ated

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gnifi

cant

and

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prov

emen

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gh-d

ose,

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ingu

al,

spec

ific

imm

unot

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ithan

extra

ctof

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gras

spo

llen

mix

ture

show

eda

sign

ifica

ntan

dcl

inic

ally

rele

vant

impr

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enti

nsu

bjec

tsw

ithgr

ass

polle

n-as

soci

ated

rhin

itis

orrh

inoc

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itis,

with

orw

ithou

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hma.

YY

YY

85Di

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273 ;2

007;

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ceAd

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ars;

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tof

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tota

lpa

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628;

imm

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156

Pros

pect

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,do

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yan

dsa

fety

ofsu

blin

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imm

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ithgr

ass

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ets

was

confi

rmed

.The

300-

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dose

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mon

stra

ted

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ifica

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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

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f

464

pap

ers

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line)

;dat

e;

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Po

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atio

nSt

udy

typ

e/

blin

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g

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com

es

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uno

ther

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gro

upP

lace

bo

gro

up

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ruit

men

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of

cons

ecut

ive

pat

ient

s

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ient

rand

om

-

izat

ion

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elin

e

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ac-

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stic

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ient

blin

ded

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lth

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ual

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pat

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86Sr

ivas

tava

274 ;

2007

;Ind

iaAl

lerg

yan

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mun

olog

ySe

ctio

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otal

patie

nts=

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imm

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hera

py;

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omiz

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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

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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

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s=

410;

imm

unot

hera

py=

307;

plac

ebo

=10

3

Pros

pect

ive,

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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

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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

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ffere

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inSL

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twee

nth

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ps.

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crea

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ase

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eat

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eto

the

treat

men

tw

ithom

aliz

umab

,rat

hert

han

toSI

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erap

y.

YY

Y

89Ib

anez

279 ;2

007;

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nCh

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icio

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Graz

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dco

nsid

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suita

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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

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plac

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YY

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91Ca

lder

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itute

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0;pl

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pect

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ingu

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gras

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acy.

Alo

nger

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acy

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tive

topl

aceb

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ring

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gras

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llen

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on.

480

480

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454

YY

YY

Y

94W

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ms28

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7;UK

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erto

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iver

sity

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any

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mat

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lerg

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otal

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imm

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py(S

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cebo

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pect

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omiz

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ptom

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and

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grou

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asse

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igh

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subl

ingu

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mun

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can

ther

efor

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man

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ento

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edia

ted

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airw

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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

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

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lth

care

pro

vid

er

blin

ded

Eq

ual

trea

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to

f

pat

ient

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rven

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n

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rvlo

et31

1 ;200

7;Fr

ance

Serv

ice

dePn

eum

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ie;

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ient

s=

74;

imm

unot

hera

py(S

LIT)

;pla

cebo

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pect

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doub

le-b

lind

plac

ebo-

cont

rolle

d

Ther

ew

asa

mar

ked

and

sign

ifica

ntde

crea

seof

the

med

icat

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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

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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

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326 ;2

006;

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ark

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ts18

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partm

ento

fRe

spira

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ases

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atie

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imm

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hera

py(S

LIT)

=31

6;pl

aceb

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Pros

pect

ive,

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ed,

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plac

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ultic

ente

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enta

blet

sw

asef

fect

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polle

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duce

drh

inoc

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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

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pect

ive,

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le-b

lind,

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omiz

ed,

plac

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cont

rolle

d

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ific

imm

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hera

pyw

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mite

depo

talle

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din

duce

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cant

clin

ical

impr

ovem

ents

vspl

aceb

o.

2020

020

YY

YY

Y

110

Mar

cucc

i369 ;

2005

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lyCh

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n4–

16ye

ars;

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ica

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atric

a;to

talp

atie

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imm

unot

hera

py(S

LIT)

=13

;pla

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=11

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pect

ive,

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le-b

lind,

rand

omiz

ed,

plac

ebo-

cont

rolle

d

SLIT

inch

ildre

nm

onos

ensi

tized

tom

ites

reve

rted

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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

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ger39

2 ;200

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nmar

kAd

ults

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ars;

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Retro

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cted

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ring

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YY

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(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

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e;

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upP

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of

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ive

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ient

s

Pat

ient

rand

om

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e

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2 ;200

4;Ca

nada

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ren

and

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icin

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lpa

tient

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plac

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Pros

pect

ive,

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omiz

ed,

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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,

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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

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gnifi

cant

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cton

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ptom

sal

one

inch

ildre

nw

ithrh

inoc

onju

nctiv

itis

togr

ass

polle

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with

apl

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2749

448

YY

YY

Y

118

Smith

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004;

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lace

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cts

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121

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inic

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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

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(thi

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ticl

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om

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e

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lth

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131

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aTh

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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

Study number in the

reference list of the

meta-analysisa

Study number in

total of 464 papers

in Medlineb Study cited

Intervention group:

immunotherapy

Control group:

placebo 95% CI

Those

showing

recovery Total

Those

showing

recovery Total RR Lower Upper %Weight

22 3 Queiros et al., 2013 70 70 0 32 65.54 4.19 1025.96 2.08

23 8 Yukselen et al., 2013 21 21 0 9 19.55 1.31 291.52 2.09

25 18 Moed et al., 2013 29 29 0 30 60.97 3.90 953.45 1.50

28 29 Creticos et al., 2013 141 588 0 196 94.65 5.92 1513.58 2.28

30 31 Didier et al., 2013 79 280 0 155 88.27 5.51 1413.78 1.96

31 40 Hylander et al., 2013 7 7 0 8 16.88 1.13 251.01 1.43

35 60 Nayak et al., 2012 40 40 0 13 27.66 1.82 420.74 2.27

38 71 Klimek et al., 2012 32 40 0 10 17.44 1.16 262.78 2.40

39 75 Ahmadiafshar et al., 2012 10 10 0 10 21.00 1.40 315.98 1.52

40 77 Swamy et al., 2012 10 20 0 10 11.00 0.71 170.64 2.00

42 101 Shamji et al., 2012 166 166 0 55 111.66 7.07 1763.26 2.28

45 117 Didier et al., 2011 136 414 0 219 144.72 9.05 2314.35 1.99

49 140 Fujimura et al., 2011 51 51 0 37 75.27 4.79 1181.71 1.76

50 142 James et al., 2011 22 22 0 22 45.00 2.90 698.44 1.52

51 144 Riechelmann et al., 2010 66 66 0 74 148.88 9.40 2358.49 1.44

52 147 Nelson et al., 2011 55 213 0 225 117.22 7.29 1885.73 1.48

57 165 Yonekura et al., 2010 20 20 0 11 23.43 1.55 353.62 1.94

58 171 Makino et al., 2010 15 15 0 9 19.38 1.30 289.18 1.87

63 187 Campbell et al., 2010 17 17 0 15 31.11 2.03 476.68 1.61

68 204 Nieminen et al., 2010 20 20 0 10 21.48 1.43 322.42 2.00

69 206 Srivastava et al., 2009 61 61 0 38 77.37 4.93 1215.23 1.87

75 228 Pauli et al., 2008 99 99 0 35 71.64 4.57 1123.47 2.24

77 242 Panzner et al., 2008 24 41 0 30 36.17 2.29 572.12 1.75

79 249 Wurtzen et al., 2008 21 21 0 21 43.00 2.77 666.52 1.52

80 252 Guimaraes Junqueir deQueiros et al., 2008

58 58 0 15 31.73 2.07 485.65 2.39

82 259 Francis et al., 2008 12 12 0 6 13.46 0.93 195.01 1.98

83 267 Moreno-Ancillo et al., 2007 51 51 0 49 99.04 6.28 1561.73 1.55

84 270 de Blay et al., 2007 51 51 0 49 99.04 6.28 1561.73 1.55

92 283 Savolainen et al., 2007 20 20 0 10 21.48 1.43 322.42 2.00

93 288 Tahamiler et al., 2007 70 70 0 67 135.04 8.53 2137.21 1.55

96 306 Charpin et al., 2007 6 17 0 15 11.56 0.71 189.36 1.61

97 310 Chakraborty et al., 2006 10 18 0 17 19.89 1.26 315.22 1.56

100 315 Creticos et al., 2006 14 14 0 11 23.20 1.54 350.45 1.69

101 319 Savolainen et al., 2006 20 20 0 10 21.48 1.43 322.42 2.00

102 320 Valovirta et al., 2006 59 59 0 29 59.50 3.81 929.54 2.03

(Continued)

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Meta-analysis: role of immunotherapy for AR

TABLE 3. Continued

Study number in the

reference list of the

meta-analysisa

Study number in

total of 464 papers

in Medlineb Study cited

Intervention group:

immunotherapy

Control group:

placebo 95% CI

Those

showing

recovery Total

Those

showing

recovery Total RR Lower Upper %Weight

103 321 Larsen et al., 2006 23 23 0 7 15.67 1.07 229.51 2.28

105 330 Passalacqua et al., 2006 28 28 0 28 57.00 3.65 890.05 1.52

106 343 Colas et al., 2006 41 41 0 19 39.52 2.56 610.36 2.06

107 344 Durham et al., 2006 204 705 0 150 87.48 5.48 1395.50 2.51

108 353 Frew et al., 2006 125 307 0 103 84.75 5.32 1350.40 2.28

111 370 Jutel et al., 2005 29 29 0 28 57.03 3.65 890.55 1.55

112 375 Ameal et al., 2005 29 29 0 28 57.03 3.65 890.55 1.55

113 384 Alvarez-Cuesta et al., 2005 25 25 0 28 56.88 3.64 888.35 1.44

114 386 Corrigan et al., 2005 36 77 0 77 73.00 4.56 1168.51 1.52

15 407 Polosa et al., 2004 15 15 0 15 31.00 2.02 475.12 1.52

119 411 Mirone et al., 2004 14 14 0 16 32.87 2.14 505.13 1.43

120 414 Crimi et al., 2004 15 15 0 15 31.00 2.02 475.12 1.52

122 421 Bufe et al., 2004 82 82 0 79 159.04 10.03 2520.76 1.55

123 422 Tonnel et al., 2004 15 15 0 17 34.88 2.26 537.12 1.43

124 424 van Neerven et al., 2004 21 21 0 21 43.00 2.77 666.52 1.52

125 428 TePas et al., 2004 12 12 0 11 23.08 1.53 348.79 1.58

126 432 Khinchi et al., 2004 39 39 0 19 39.50 2.56 610.00 2.03

127 435 Pajno et al., 2003 15 15 0 15 31.00 2.02 475.12 1.52

128 437 Wuthrich et al., 2003 10 10 0 10 21.00 1.40 315.98 1.52

132 451 Polosa et al., 2003 15 15 0 15 31.00 2.02 475.12 1.52

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).

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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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