sub lingual immunotherapy cochrane sys rev july 2011 fulltext

Sublingual immunotherapy for treating allergic conjunctivitis(Review)

Calderon MA, Penagos M, Sheikh A, Canonica GW, Durham S

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2011, Issue 7

http://www.thecochranelibrary.com

Sublingual immunotherapy for treating allergic conjunctivitis (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

17DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 1 Total ocular symptom scores. . 87Analysis 1.2. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 2 Itchy/Gritty eyes. . . . . . 89Analysis 1.3. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 3 Watery eyes. . . . . . . . 90Analysis 1.4. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 4 Red eyes. . . . . . . . . 91Analysis 1.5. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 5 Swollen eyes. . . . . . . . 92Analysis 1.6. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 6 Eye drops. . . . . . . . . 93Analysis 1.7. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 7 Combined symptom-medication

scores. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Analysis 1.8. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 8 Conjunctival immediate allergen

sensitivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Analysis 1.9. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 9 Total ocular symptom scores: Seasonal

and perennial. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95Analysis 1.10. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 10 Total ocular symptom scores: Adults

and children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Analysis 1.11. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 11 Total ocular symptom scores:

Publication year. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99Analysis 1.12. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 12 Total ocular symptom scores:

Treatment > 12 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101Analysis 1.13. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 13 Total ocular symptom scores: Fixed-

effects model. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103104APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .107HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .107CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .108DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

iSublingual immunotherapy for treating allergic conjunctivitis (Review)


[Intervention Review]

Sublingual immunotherapy for treating allergic conjunctivitis

Moises A Calderon1, Martin Penagos1, Aziz Sheikh2, Giorgio W Canonica3, Stephen Durham1

1Department of Allergy and Respiratory Medicine, Royal Brompton Hospital, London, UK. 2Centre for Population Health Sciences,University of Edinburgh, Edinburgh, UK. 3Allergy and Respiratory Diseases Clinic, Department of Internal Medicine (DIMI), Uni-versity of Genoa, Genoa, Italy

Contact address: Moises A Calderon, Department of Allergy and Respiratory Medicine, Royal Brompton Hospital, Imperial CollegeSchool of Medicine at the National Heart and Lung Institute, London, SW3 6LY, UK. [email protected].

Editorial group: Cochrane Eyes and Vision Group.Publication status and date: New, published in Issue 7, 2011.Review content assessed as up-to-date: 18 January 2011.

Citation: Calderon MA, Penagos M, Sheikh A, Canonica GW, Durham S. Sublingual immunotherapy for treating allergic conjunc-tivitis. Cochrane Database of Systematic Reviews 2011, Issue 7. Art. No.: CD007685. DOI: 10.1002/14651858.CD007685.pub2.


A B S T R A C T

Background

Allergic ocular symptoms, although frequently trivialised, are common and represent an important comorbidity of allergic rhinitis.Sublingual Immunotherapy (SLIT) is an effective and well-tolerated treatment for allergic rhinitis, but its effects on symptoms of ocularallergy have not been well established.

Objectives

To evaluate the efficacy of SLIT compared with placebo for reductions in ocular symptoms, topical ocular medication requirementsand conjunctival immediate allergen sensitivity.

Search strategy

We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 1),MEDLINE (January 1950 to January 2011), EMBASE (January 1980 to January 2011), Latin American and Caribbean Literature onHealth Sciences (LILACS) (January 1982 to January 2011), Web of Science (January 1970 to January 2011), Biosis Previews, (January1979 to January 2011), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (January 2011), ClinicalTrials.gov (www.clinicaltrials.gov) (January 2011), the Australian New Zealand Clinical Trials Registry (ANZCTR) (www.actr.org.au) (July 2010),SCOPUS (November 2008) and the UK Clinical Trials Gateway (January 2010). There were no language or date restrictions in thesearch for trials. All electronic databases except for SCOPUS, the UK Clinical Trials Gateway and ANZCTR were last searched on 19January 2011.

Selection criteria

Randomised controlled trials (RCTs), double-masked and placebo controlled, which evaluated the efficacy of SLIT in patients withsymptoms of allergic rhinoconjunctivitis (ARC) or allergic conjunctivitis (AC).

Data collection and analysis

The primary outcome was the total ocular symptom scores. Secondary endpoints included individual ocular symptom scores (such asitchy eyes, red eyes, watery eyes, swollen eyes), ocular medication scores (eye drops) and conjunctival immediate allergen sensitivity(CIAS). Data were analysed and reported as standardised mean differences (SMDs) using Review Manager software.

1Sublingual immunotherapy for treating allergic conjunctivitis (Review)


mailto:[email protected]

http://www.controlled-trials.com/


http://www.clinicaltrials.gov

http://www.actr.org.au

Main results

Forty-two trials (n = 3958 total participants; n= 2011 SLIT and n = 1947 placebo) had available data to evaluate the efficacy of SLITon AC and were included in the meta-analyses. Heterogeneity among studies (I2 statistic) was around 50% or below for all endpoints.Sublingual immunotherapy induced a significant reduction in both total ocular symptom scores (SMD -0.41; 95% confidence interval(CI) -0.53 to -0.28; P < 0.00001; I2 = 59%) and individual ocular symptom scores for red eyes (SMD -0.33; 95% CI -0.45 to -0.22;P < 0.00001; I2 = 27%), itchy eyes (SMD -0.31; 95% CI -0.42 to -0.20; P < 0.00001; I2 = 46%) and watery eyes (SMD -0.23; 95%CI -0.34 to -0.11; P < 0.0001; I2 = 42%) compared to placebo. Those participants having active treatment showed an increase in thethreshold dose for the conjunctival allergen provocation test (SMD 0.35; 95% CI 0.00 to 0.69; P = 0.05; I2 = 43%). No significantreduction was observed in ocular eye drops use (SMD -0.10; 95% CI -0.22 to 0.03; P = 0.13; I2 = 34%).

Authors’ conclusions

Overall, SLIT is moderately effective in reducing total and individual ocular symptom scores in participants with ARC and AC.There were however some concerns about the overall quality of the evidence-base, this relating to inadequate descriptions of allocationconcealment in some studies, statistical heterogeneity and the possibility of publication bias. There is a need for further large rigorouslydesigned studies that study long-term effectiveness after discontinuation of treatment and establish the cost-effectiveness of SLIT.

P L A I N L A N G U A G E S U M M A R Y

Sublingual immunotherapy (tablets, spray or drops under the tongue) to treat inflammation of the conjunctiva due to allergy

Conjunctivitis means inflammation of the conjunctiva. The conjunctiva is the thin ’skin’ that covers the white part of the eyes and theinside of the eyelids. Allergic conjunctivitis is the inflammation of the conjunctiva due to allergy. The most common cause is an allergyto pollen during the hay fever season. Symptoms include red eyes, itching, increased tearing and swelling of the conjunctiva and eyelids.If allergic conjunctivitis is combined with nasal allergy, the condition is termed allergic rhinoconjunctivitis. When medications do notprovide enough relief another option is immunotherapy, which builds immunity to the allergen causing the reaction. Immunotherapycan be given under the tongue, nasally or by injection. This review included 42 trials with a total of 3958 participants with allergicconjunctivitis; 2011 who had sublingual immunotherapy and 1947 who had placebo. This review found that sublingual immunotherapy(that is, administered under the tongue) can reduce symptoms of allergic conjunctivitis.



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Sublingual immunotherapy versus placebo for allergic conjunctivitis

Patient or population: patients with allergic conjunctivitisSettings: clinical allergy unitsIntervention: sublingual immunotherapy

Outcomes Illustrative comparative risks* (95% CI) Relative effect(95% CI)

No of Participants(studies)

Quality of the evidence(GRADE)

Comments

Assumed risk Corresponding risk

Control Sublingual immunother-apy

Total ocular symptomscoresSymptom scores

The mean total ocularsymptom scores rangedacross control groupsfrom0.01 to 268 points

The mean total ocularsymptom scores in the in-tervention groups was0.41 standard deviationslower(0.53 to 0.28 lower)

3399(36 studies)

!!!"

moderate1,2

SMD -0.41 (-0.53 to -0.28)

Itchy/Gritty eyesSymptom scores

The mean itchy/grittyeyes ranged across con-trol groups from0.004 to 121 points

The mean itchy/grittyeyes in the interventiongroups was0.31 standard deviationslower(0.42 to 0.2 lower)

3020(28 studies)

!!!"

moderate3

SMD -0.31 (-0.42 to -0.2)

Watery eyesSymptom scores

The mean watery eyesranged across controlgroups from0.023 to 44.13 points

The mean Watery eyesin the intervention groupswas0.23 standard deviationslower(0.34 to 0.11 lower)

2641(21 studies)

!!!"

moderate4

SMD -0.23 (-0.34 to -0.11)

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Red eyesSymptom scores

The mean red eyesranged across controlgroups from0.02 to 147 points

The mean red eyes in theintervention groups was0.33 standard deviationslower(0.45 to 0.22 lower)

1211(20 studies)

!!!"

moderate5

SMD -0.33 (-0.45 to -0.22)

Eye dropsSymptom scores

The mean eye dropsranged across controlgroups from0.17 to 8 points

Themean eye drops in theintervention groups was0.1 standard deviationslower(0.22 lower to 0.03higher)

1038(13 studies)

!!!"

moderate6

SMD -0.1 (-0.22 to 0.03)

Combined symptom-medication scoresSymptom scores

The mean com-bined symptom-medica-tion scores ranged acrosscontrol groups from0.6 to 151.1 points

The mean com-bined symptom-medica-tion scores in the inter-vention groups was0.21 standard deviationslower(0.55 lower to 0.13higher)

351(3 studies)

!!!"

moderate7

SMD -0.21 (-0.55 to0.13)

Conjunctival immediateallergen sensitivitySymptom scores

The mean conjunctivalimmediate allergen sensi-tivity ranged across con-trol groups from2.7 to 33.26 points

The mean conjunctivalimmediate allergen sen-sitivity in the interventiongroups was0.35 standard deviationshigher(0 to 0.69 higher)

250(4 studies)

!!!"

moderate8,9

SMD 0.35 (0 to 0.69)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on theassumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).CI: Confidence interval;

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GRADE Working Group grades of evidenceHigh quality: Further research is very unlikely to change our confidence in the estimate of effect.Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.Very low quality: We are very uncertain about the estimate.

1 All the included studies are double-masked and placebo controlled RCTs. Due to the nature of the disease, the majority of the studiesaimed to treat rhinoconjunctivitis not the ocular component by itself; only one study was specifically designed to evaluate justconjunctivitis. However, in all the studies eye symptom scores were planned to be assessed as a primary or secondary endpoint.

2,7 Significant heterogeneity was found (I2 = 59%)3,5,8 Relatively few patients were included in some studies4,6 Publication bias is likely for this outcome9 Publication bias cannot be assessed for this outcome* Data were skewed in most studies, which can limit the validity of the meta-analysis.

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B A C K G R O U N D

Description of the condition

Allergic inflammation involving the eye is common and may bethe most prominent or, in some cases, the only feature of allergy(Bielory 2008a). The prevalence of ocular allergies in the generalpopulation is estimated to be up to 40% in the United States(Singh 2010) and 18% in the United Kingdom (Buckley 1998).Allergic conjunctivitis (AC) is strongly linked to allergic rhinitis(AR); approximately 90% of patients with AR experience at leastone day of ocular symptoms per week (Berger 2005; Canonica2007; Torkildsen 2009). Seasonal allergic conjunctivitis (SAC) isdue to the direct exposure of the ocular mucosal surfaces to envi-ronmental allergens, such as pollens from trees, grasses and weeds,which interact with the pollen-specific immunoglobulin E (IgE)found on the mast cells of the eye (Bielory 2002). Perennial aller-gic conjunctivitis (PAC) also exhibits an IgE mast cell-mediatedhypersensitivity to airborne allergens, more frequently perennialhousehold allergens such as dust mites, moulds and animal dan-der. Common conjunctival symptoms are itching, tearing, rednessand sometimes burning. Both eyes are typically affected simulta-neously and, quite often, a family history of hay fever or atopy iselicited (Bielory 2007b; Bielory 2008a). Visual impairment is un-common, with blurring of vision being the most common cornealsymptom (Bielory 2007a).

Description of the intervention

Sublingual immunotherapy (SLIT) has been demonstrated tobe clinically effective. It is safe and provides an antigen-specificprotective immune effect observed in several randomised con-trolled trials (RCTs) including patients with allergic rhinitis (AR)(Radulovic 2010; Wilson 2005). In recent years, several RCTs eval-uating the efficacy of SLIT for allergic rhinoconjunctivitis (ARC)have addressed its particular effect on ocular symptoms. A signif-icant reduction in eye symptoms, conjunctival sensitivity, ocularrescue medication requirements and an improvement in rhinocon-junctivitis quality of life questionnaire scores (RQLQ) have beenreported in a study using SLIT with grass pollens (Durham 2007a)and house dust mites (Mortemousque 2003). Regarding perennialAC, a RCT demonstrated that SLIT effectively increased the anti-genic threshold required to obtain a positive conjunctival provoca-tion test to house dust mites (Mortemousque 2003). Despite theseobservations, it is unclear whether this effect is observed amongall available studies.

How the intervention might work

It has been proposed that during SLIT, allergen is captured withinthe oral mucosa by Langerhans-like dendritic cells. Subsequently,

dendritic cells mature and migrate to proximal draining lymphnodes (for example submaxillary, superficial cervical and internaljugular) as a consequence of changes in expression of surface recep-tors (Moingeon 2006). Those lymph nodes represent specialisedmicro-environments favouring the induction of mucosal toler-ance through the production of blocking IgG antibodies (IgG2bin mice) and the induction of T lymphocytes with suppressivefunction (Moingeon 2006). Large-scale trials have confirmed theinduction of allergen-specific IgG antibodies after several weeksof therapy, probably SLIT dose-dependent (Dahl 2007; Scadding2009; Torres-Lima 2002). There is no early suppression of aller-gen-specific IgE antibodies and a transient early increase in specificIgE antibodies is observed. Current models of subcutaneous im-munotherapy propose the induction of antigen-specific regulatoryT cells (Scadding 2009). A study showed that SLIT induces regu-latory T cell suppression through IL-10 during the early phase andspecific non-reactivity and immune deviation of allergen-specificT cells during the later phase of therapy (Bohle 2007).

Why it is important to do this review

Specific immunotherapy is a disease-modifying treatment, whichreduces symptoms in people with AR and asthma (Abramson2003; Calderon 2007; Dahl 2007; Didier 2007; Penagos 2008).Although SLIT might be potentially effective in reducing allergicocular symptoms (Durham 2007a; Mortemousque 2003), we areunclear whether these effects are observed consistently across stud-ies. An evaluation of its effects on ocular symptoms in the contextof RCTs could provide an alternative treatment for people withAC.

O B J E C T I V E S

To evaluate the efficacy of SLIT versus placebo in patients withAC or ARC in improving ocular outcomes.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included randomised, double-masked placebo controlled trialsof SLIT.



Types of participants

All patients (children and adults) presenting with AC or ARC wereincluded. People with both seasonal and perennial forms of thedisease were included.

Types of interventions

We included studies using SLIT administered either by drops ortablets compared to placebo.

Types of outcome measures

We evaluated the effect of interventions on primary and secondaryoutcomes after at least one pollen season for seasonal allergens andfor at least six consecutive months for perennial allergens.

Primary outcomes

1. Total ocular symptom scores

Secondary outcomes

1. Individual ocular symptom scores (grittiness, redness,itching, watery eyes, chemosis and ocular swelling)

2. Ocular medication scores (eye drops use)3. Conjunctival immediate allergen sensitivity4. Combined symptom medication scores

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Tri-als (CENTRAL) 2011, Issue 1, part of The Cochrane Librarywww.thecochranelibrary.com (accessed 19 January 2011), MED-LINE (January 1950 to January 2011), EMBASE (January1980 to January 2011), Latin American and Caribbean Liter-ature on Health Sciences (LILACS) (January 1982 to January2011), Web of Science (January 1970 to January 2011), BiosisPreviews (January 1979 to January 2011), the metaRegister ofControlled Trials (mRCT) (www.controlled-trials.com) (January2011), ClinicalTrials.gov (www.clinicaltrials.gov) (January 2011),the Australian New Zealand Clinical Trials Registry (ANZCTR)(www.actr.org.au) (July 2010), SCOPUS (November 2008) andthe UK Clinical Trials Gateway (January 2010). There were nolanguage or date restrictions in the search for trials. All electronicdatabases except for SCOPUS, the UK Clinical Trials Gatewayand ANZCTR were last searched on 19 January 2011. SCOPUShas ceased to be searched as access to this resource is no longeravailable. The UK Clinical Trials Gateway search has been super-seded by searching global clinic trials registers.

See: Appendices for details of search strategies for CENTRAL(Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix3), LILACS (Appendix 4), Web of Science (Appendix 5), BiosisPreviews (Appendix 6), mRCT (Appendix 7), ClinicalTrials.gov(Appendix 8), ANZCTR (Appendix 9), UKCTG (Appendix 10)and Scopus (Appendix 11).

Searching other resources

1. Developed a database of first and last authors of potentiallyeligible studies and The Science Citation Index Expanded (SCI-EXPANDED, 1945 to the present) was searched using thesenames for additional studies

2. Compiled a database of international experts in SLIT3. Searched bibliographies of identified studies4. Contacted relevant product manufacturers

Data collection and analysis

Selection of studies

Two authors (MC and MP) independently reviewed titles and ab-stracts from literature searches for relevant trials for full review.The full text copies of all potentially eligible studies were obtainedand subjected to independent review using the inclusion criteriadetailed above. At this stage, any study rejected was documentedin the ’Characteristics of excluded studies’ table. The percentageagreement between the investigators for the assessment of inclu-sion was reported. We resolved disagreement by discussion be-tween both of the authors; in the case of consensus not beingreached, a third author (SRD) was involved and, if necessary, ar-bitrated (Dawson 2004; Higgins 2011a).

Data extraction and management

Two authors (MP and MC) independently extracted data using asuitably adapted version of the data extraction form developed bythe Cochrane Eyes and Vision Group. We resolved disagreementsby discussion between both of the authors; in case of consensus notbeing reached, a third author (SRD) was involved and, if necessary,arbitrated.

Assessment of risk of bias in included studies

Two authors (MC and MP) working independently assessed theincluded studies for sources of systematic bias in trials accordingto the guidelines in Chapter 8 of the Cochrane Handbook for Sys-tematic Reviews of Interventions (Higgins 2011b). The agreementof authors on risk of bias assessment was measured (Dawson 2004;Higgins 2011b); disagreements were resolved by discussion and,if necessary, with the involvement of a third author (SRD).






http://www.clinicaltrials.gov

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We considered the following domains for assessing risk of bias(The Cochrane Collaboration’s tool) (Higgins 2011b).1. Sequence generation: describe the method used to generate theallocation sequence in sufficient detail to allow an assessment ofwhether it should produce comparable groups.2. Allocation concealment: describe the method used to concealthe allocation sequence in sufficient detail to determine whetherintervention allocations could have been foreseen in advance of,or during, enrolment.3. Blinding (masking) of participants, personnel and outcome assessors:describe all measures used, if any, to mask study participants andpersonnel from knowledge of which intervention a participantreceived. Provide any information relating to whether the intendedmasking was effective.4. Incomplete outcome data: describe the completeness of outcomedata for each main outcome, including attrition and exclusionsfrom the analysis. State whether attrition and exclusions were re-ported, the numbers in each intervention group (compared withtotal randomised participants), reasons for attrition or exclusionswhere reported, and any re-inclusions in analyses performed bythe review authors.5. Selective outcome reporting: state how the possibility of selectiveoutcome reporting was examined by the review authors, and whatwas found.6. Other sources of bias: state any important concerns about biasnot addressed in the other domains in the tool.

Measures of treatment effect

We used Review Manager 5.1 (RevMan 2011) for data analysisand quantitative data synthesis. For continuous data (total and in-dividual symptom scores, ocular medication scores and conjunc-tival immediate allergen sensitivity), we calculated individual and,if appropriate, pooled statistics as mean differences (MDs) or stan-dardised mean differences (SMDs) with 95% confidence interval(CI). Quantitative analyses of outcomes were, wherever possible,on an intention-to-treat basis.

Unit of analysis issues

Allergic conjunctivitis is almost always secondary to environmen-tal allergens exposition and, therefore, usually presents with bilat-eral symptoms (Bielory 2007a; Jackson 1991). Randomised con-trolled trials on SLIT efficacy report ocular symptoms in partici-pants as only one score at the ocular level (Murdoch 1998). Conse-quently, analyses were conducted on individuals rather than eyes.

Dealing with missing data

We contacted trial authors if details about study design or descrip-tive statistics for outcomes were not presented in the paper (mean,standard deviation (SD)). If the authors did not respond withina reasonable time (six to eight weeks), we conducted the reviewbased on available information.

Assessment of heterogeneity

We tested for inconsistency using the I2 statistic. Substantial het-erogeneity was assumed if I2 was greater than 40% (that is morethan 40% of the variability in the outcome between trials couldnot be explained by sampling variation) (Deeks 2011; Higgins2002; Higgins 2003; Sutton 2008).

Assessment of reporting biases

We looked for evidence of publication bias graphically using funnelplots and statistically by means of the Begg and the Egger tests, if asufficient number of trials was identified for the primary outcome(Begg 1994; Egger 1997; Higgins 2011b; Sterne 2001).

Data synthesis

If there was significant heterogeneity (I2 > 40%), the random-effects model was used; otherwise we used the fixed-effect model.

Subgroup analysis and investigation of heterogeneity

In the event of uncovering significant heterogeneity, we investi-gated the heterogeneity using subgroup analyses. Our subgroupsof interest were:

1. seasonal or perennial conjunctivitis;2. treatment duration;3. allergen dose (daily dose in micrograms, if this was

available);4. participants’ age group (children less than 18 years of age or

adults).

Sensitivity analysis

The sensitivity analysis was performed by: (i) determining theimpact of exclusion of studies with lower methodological quality;and (ii) by using different statistical methods (fixed-effect andrandom-effects models).

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excludedstudies.

Results of the search

The electronic searches yielded a total of 1361 titles and abstracts(Figure 1). After deduplication, the Trials Search Co-ordinatorscanned 946 records and discarded 135 records because they werenot relevant to the scope of the review. We screened the titles and



abstracts of the remaining 811 references. We initially excludednine reports as not being relevant to the review and then evaluated109 papers in detail.

Figure 1. Results from searching for studies for inclusion in the review



We identified 57 studies (8.6%) that met the inclusion criteria.Of these, 15 studies did not have extractable data and thereforewere not included in the meta-analysis. Forty-two studies (5.1%)had available data to evaluate the efficacy of SLIT on AC and wereincluded for the analysis.We excluded 52 studies from this review after further reading.Reasons for exclusion were: outcomes of interest not evaluated(n = 12), studies not controlled with placebo (n = 12), designdifferences (n = 8), outcomes reported in other studies (n = 8),not double-masked (n = 6), trials designed to evaluate safety (n= 2), reviews (n = 2), studies non-randomised (n = 1) and otherinclusion criteria (n = 1). When an outcome of interest was notreported in the full text version of any of the papers, we contactedthe authors to ask them whether the endpoint had been evaluated.

Because some of the studies were primarily designed to evaluatethe effects of SLIT on allergic rhinitis, 12 authors stated that ocularoutcomes were not measured.

Included studies

Characteristics of the 42 included trials are provided in Table1. Thirty-eight studies were conducted in Europe, one in bothEurope and Canada, one in China, one in Turkey and one inCanada. Of the 42 included studies, 40 (95%) were publishedin English, one (2.5%) in Chinese and one (2.5%) in Spanish.Eleven studies were published between 1994 and 1999, 13 from2000 to 2005 and 18 from 2006 up to the last search.

Table 1. Characteristics of included randomised, double-masked, placebo controlled studies

Study Year Participantsage

Mean age orrange

nrandomised

Allergen Allergentype

Presentation Tx duration(months)

Andre 2003 Children andadults

35.1 110 Ragweed Seasonal Both 6.5

Ariano 2001 Adults 34.8 20 Cupressus ari-zonica

Seasonal Drops 8

Aydogan 2007 Children 7.28 18 Mites Perennial Drops 12

Bowen 2004 Children andadults

36 83 Ambrosiaeliator

Seasonal Drops 3

Bufe 2004 Children 9.6 161 Grass mix Seasonal Drops 12

Bufe 2009 Children 10.1 253 Phleumpratense

Seasonal Tablets 7

Cao 2007 Children 8.2 278 Mites Perennial Drops 6

Casanovas 1994 Adults 25 15 Olea europaea Seasonal Drops 4

Dahl Allergy 2006 Adults 36.5 634 Phleumpratense

Seasonal Tablets 5

Dahl JACI 2006 Adults 34.5 114 Phleumpratense

Seasonal Tablets 8

de Blay 2007 Children andadults

24.9 118 Grass mix Seasonal Drops 10



Table 1. Characteristics of included randomised, double-masked, placebo controlled studies (Continued)

Didier 2007 Adults 29 628 Grass mix Seasonal Tablets 5

Dubakiene 2003 Children andadults

10-61 119 Tree pollen Seasonal Drops 4

Durham 2006 Adults 36 855 Phleumpratense

Seasonal Tablets 4.5

Feliziani 1995 Adults 14-48 34 Grass mix Seasonal Drops 4

Hirsch 1997 Children 11 30 Mites Perennial Drops 12

Horak 1998 Adults 33 41 Betula alba Seasonal Drops 24

Khinchi 2004 Adults 30 71 Birch pollen Seasonal Drops 36

La Rosa 1999 Children 10 41 Parietaria ju-daica

Seasonal Drops 24

Moreno-Ancillo

2007 Children andadults

28.6 105 Olea europaea Seasonal Drops 8

Morte-mousque

2003 Children andadults

24 60 Mites Perennial Drops 24

Ott 2009 Children andadults


Palma-Carlos

2006 Adults 30.3 33 Grass mix Seasonal Tablets 24

Panzner 2008 Children andadults


Passalacqua 1998 Children andadults

27.2 20 Mites Perennial Tablets 24

Passalacqua 1999 Adults 33.2 30 Parietaria ju-daica

Seasonal Drops 5

Passalacqua 2006 Adults 31.2 68 Mites Perennial Tablets 24

Pfaar 2008 Adults 33.8 185 Grass mix Seasonal Drops 24

Pradalier 1999 Children andAdults

29.7 126 Grass mix Seasonal Drops 4.5

Purello-D’Ambrosio

1999 Adults 32 30 Parietaria ju-daica

Seasonal Drops 4



Table 1. Characteristics of included randomised, double-masked, placebo controlled studies (Continued)

Rolinck-Werning-haus

2004 Children 3-14 97 Grass mix Seasonal Drops 32

Röder 2007 Children 12.9 204 Grass mix Seasonal Drops 24

Sanchez-Palacios

2001 Adults 24.5 40 Cat Perennial Drops 12

Smith 2004 Adults 40 180 Grass mix Seasonal Both 24

Torres-Lima 2002 Adults 34 56 Phleumpratense

Seasonal Drops 18

Troise 1995 Adults 34.8 31 Parietaria ju-daica

Seasonal Drops 10

Valovirta 2006 Children 9 98 Tree pollen Seasonal Drops 19

Vervloet 2007 Adults 39 76 Juniperusashei

Seasonal Drops 4

Voltolini 2001 Adults 39 30 Tree pollen Seasonal Drops 12

Vourdas 1998 Children 12 66 Olea europaea Seasonal Drops 24

Wahn 2008 Children 10.9 278 Grass mix Seasonal Tablets 5

Wuthrich 2003 Children 7.9 28 Grass mix Seasonal Drops 24

Thirty-five (88%) of the included studies evaluated the efficacyof seasonal allergens and seven trials were with perennial allergens(12%). Nineteen (45%) used grass pollen extracts, 10 (24%) trialsevaluated tree pollen extracts, six (14.5%) mites, six (14.5%) weedsand one (2%) was a study assessing the efficacy of a standardised catextract. All studies compared SLIT with placebo during a double-masked treatment.Thirty-one (74%) studies administered the extracts as sublingualdrops, nine (21%) as tablets and two (5%) both drops during thebuild-up phase and tablets subsequently for maintenance.A total of 3958 participants with a median age of 29.7 years weretreated for a median duration of 12 months (range 3 to 36). Sub-lingual immunotherapy was given to 2011 (50.8%) participantsand placebo to 1947 (49.2%).Two studies (Torres-Lima 2002; Wuthrich 2003) were includedin the systematic review but not in the pooled analyses; this wasbecause the trial authors provided us with raw data which did not

allow us to perform calculations of arithmetic means and SDs.

Imputation of missing variance data

No imputation of data was performed in the case of missing out-comes. All the authors were contacted and if the information wasnot available, the study was excluded from the meta-analysis butincluded in the systematic review.

Risk of bias in included studies

The Cochrane tool was used in this review to assess the risk ofbias of the included studies. All the studies were reviewed inde-pendently by two authors (MC and MP) and then the evaluationswere compared. We resolved disagreements by discussion. Con-sultation with a third author (SRD or AS) was requested whennecessary. A methodological quality summary (Figure 2) and agraph are presented (Figure 3).



Figure 2. Methodological quality summary: review authors’ judgements about each methodological qualityitem for each included study.



Figure 3. Methodological quality graph: review authors’ judgements about each methodological quality

item presented as percentages across all included studies.

Allocation

Twenty-one studies described the method used to generate theallocation sequence (50%) and 12 trials described the methodsused to conceal the allocation sequence (29%).

Blinding

Thirty-eight studies (91%) described the measures used to maskstudy participants and personnel from knowledge of which inter-vention a participant received.

Incomplete outcome data

Forty studies (95%) described the completeness of outcome datafor each main outcome, including attrition and exclusions fromthe analysis.

Selective reporting

For 40 studies (95%) we stated how the possibility of selectiveoutcome reporting was examined by the review authors and whatwas found.

Other potential sources of bias

For 33 studies (79%) we stated any important concerns about biasnot addressed in the other domains in the tool. As an additional

source of bias in the meta-analytic process, we found that moststudies, that is 22 out of 36 reporting total symptom scores, hadskewed data in the treatment group (n = 12), in the control group(n = 2), or both (n = 8). Skewness was identified as a mean totalsymptom score inferior to one SD, nil being the lowest possiblevalue (Deeks 2011). Although in some individual studies data wereanalysed correctly, that is using non-parametric tests, the need toinput skewed data, expressed as mean and SD, in the meta-analysismay limit the validity of our findings (Cochrane open learningmaterial 2002). Skewness was also found in 14/28 studies for ’itchygritty eyes’, 19/21 studies for ’watery eyes’, 18/20 studies for ’redeyes’, and 11/13 studies for ’ocular medication scores’.

Effects of interventions

See: Summary of findings for the main comparison Sublingualimmunotherapy versus placebo for allergic conjunctivitis

Effects of SLIT on total ocular symptom scores

Thirty-six of the included trials assessed this outcome. Of 3399participants, 1725 received SLIT and 1674 placebo. Sublingualimmunotherapy induced a significant reduction in total ocularsymptom scores compared to placebo (SMD -0.41; 95% CI - 0.53to - 0.28; P < 0.00001). Substantial inter-study heterogeneity wasfound (I2 = 59%) (Analysis 1.1).



Assessment according to the allergen type for those studies usingSLIT with seasonal allergens (n = 30) showed a significant reduc-tion in total ocular symptom scores compared to placebo (SMD-0.38; 95% CI -0.50 to -0.25; P < 0.00001; I2 = 58%) but notperennial allergens (n = 6) (SMD -0.52; 95% CI -1.05 to 0.01; P= 0.05; I2 = 70%) (Analysis 1.9).Subgroup analysis by age groups was performed: in adults 27 stud-ies including 2542 participants (SLIT = 1304 and placebo = 1238)showed a significant reduction in total ocular symptom scores(SMD -0.48; 95% CI - 0.63 to - 0.32; P < 0.00001; I2= 64%).In children, nine studies including 857 participants (SLIT = 421and placebo = 436) also showed a significant reduction in totalocular symptom scores (SMD -0.27; 95% CI - 0.46 to - 0.07; P= 0.007; I2= 39%) (Analysis 1.10). The impact of the duration oftreatment was evaluated. Twenty-six studies that gave treatmentfor 12 months or less, including 2888 participants (SLIT = 1468and placebo = 1420), showed a significant reduction in total oc-ular symptom scores (SMD -0.40; 95% CI - 0.53 to - 0.27; P< 0.00001; I2= 58%). Ten trials gave treatment for 13 monthsor more, including 511 participants (SLIT = 257 and placebo =254), and showed a significant reduction in total ocular symptomscores (SMD -0.43; 95% CI - 0.76 to - 0.10; P = 0.01; I2= 68%)(Analysis 1.12).

Effects of SLIT on individual ocular symptom scores

Itchy gritty eyes: 28 trials evaluated this outcome in 3020 par-ticipants (1540 SLIT and 1480 placebo). The overall effect acrossthese trials was a significant reduction in eye itchiness in the par-ticipants treated with SLIT (SMD -0.31; 95% CI -0.42 to -0.20;P < 0.00001). No significant inter-study heterogeneity was found(I2 = 46%). For two studies, this was the primary ocular out-come and data for total ocular symptom scores were not reported(Passalacqua 2006; Röder 2007) (Analysis 1.2).Watery eyes: 21 studies assessed the efficacy of both SLIT andplacebo in 2641 participants; 1344 received SLIT and 1297placebo. There was a significant reduction in watery eyes in thoseparticipants who received SLIT compared to placebo (SMD -0.23;95% CI -0.34 to -0.11; P < 0.0001; I2 = 42%) (Analysis 1.3).Red eyes: 20 trials including 1211 participants reported eye red-ness as an outcome. Six hundred and twenty-four participantsreceived SLIT and 587 placebo. The overall effect across thesetrials showed a significant reduction in the scores of the partici-pants treated with SLIT (SMD -0.33; 95% CI -0.45 to -0.22; P <0.00001). No significant inter-study inconsistency was found (I2

= 27%) (Analysis 1.4).Ocular swelling: only two studies reported ocular swelling as anoutcome. One hundred and thirty-two participants were consid-ered of which 66 received SLIT and 66 received placebo. No dif-ference in effect was observed between the treatments (SMD -

0.23; 95% CI -1.19 to 0.72; P = 0.63). Inter-study inconsistencywas significant (I2 = 83%) (Analysis 1.5).

Effects of SLIT on combined symptom medication scores

Three studies reported combined symptom medication scoresas an outcome; 351 participants were analysed. Sublingual im-munotherapy was given to 176 participants and 175 receivedplacebo. There was a marginal non-significant reduction in thecombined scores in those patients receiving SLIT (SMD -0.21;95% CI -0.55 to 0.13; P = 0.22). Inconsistency among studieswas significant (I2 = 59%) (Analysis 1.7). In two studies this wasthe primary ocular outcome and total ocular symptom scores werenot reported (Bufe 2004; Pfaar 2008).

Effects of SLIT on ocular medication scores

Thirteen trials including 1038 participants reported the use ofeye drops; 560 received SLIT and 478 were treated with placebo.There were not significant differences between the interventions(SMD -0.10; 95% CI -0.22 to 0.03; P = 0.13). No significantinter-study inconsistency was found (I2 = 34%) (Analysis 1.6).

Effects of SLIT on the conjunctival immediate allergensensitivity

Four trials including 250 participants evaluated this outcome. Sub-lingual immunotherapy was given to 130 participants and 120 re-ceived placebo. Those participants in the active treatment showedan increase in the threshold dose for the conjunctival allergenprovocation test (SMD 0.35; 95% CI 0.00 to 0.69; P = 0.05).No significant inter-study inconsistency was found (I2 = 43%)(Analysis 1.8).

Analysis of publication bias

Studies excluded for unavailable data

We excluded 14 out of 54 trials which met the inclusion criteriaas no data were available for them.

Funnel plots

To test for the possibility of publication bias in the review, funnelplots were created for total ocular symptom scores. These plotswere reasonably symmetrical and there did not appear to be apaucity of smaller trials with small or absent symptoms reductioneffect (Figure 4).



Figure 4. Funnel plot of comparison: 1 Sublingual immunotherapy versus placebo, outcome: 1.1 Totalocular symptom scores.

Egger’s and Begg’s tests

The analysis of small study bias for total ocular symptom scoresusing the Egger’s test was not statistically significant (P = 0.144).However, the Begg’s test showed a significant publication bias (P= 0.007). Both tests were not significant in other analyses.

Tertile analysis based on publication year

A post hoc tertile analysis was done to determine the effect of theyear of publication of trials on the efficacy of SLIT. This analysiswas done for all trials evaluating total ocular symptom scores (Analysis 1.11). The SMD of the latest tertile (2006 to 2009) wascompared with that of the earliest tertile (1994 to 1999); there wasno significant difference for total symptom scores between them.

Sensitivity analysis

Sensitivity analyses were performed to assess the robustness of theresults, which were unchanged whether the fixed-effect model orrandom-effects model was used (Analysis 1.13 and Table 2).

Table 2. Sensitivity analysis using the random-effects and the fixed-effect models

Outcome orSubgroup

Studies n Random-effects model Fixed-effect model

I2 SMD, 95% CI I2 SMD, 95% CI

1.1 Total ocularsymptom scores

36 3399 59% -0.41 (-0.53 to -0.28) 59% -0.38 (-0.44 to -0.31)



Table 2. Sensitivity analysis using the random-effects and the fixed-effect models (Continued)

1.2 Itchy/grittyeyes

28 3020 45% -0.31 (-0.42 to -0.20) 46% -0.32 (-0.40 to -0.25)

1.3 Watery eyes 21 2641 42% -0.23 (-0.34 to -0.11) 42% -0.27 (-0.34 to -0.19)

1.4 Red eyes 20 1211 27% -0.34 (-0.48 to -0.20) 27% -0.33 (-0.45 to -0.22)

1.5 Swollen eyes 2 132 83% -0.23(-1.19 to 0.72) 83% -0.03 (-0.38 to 0.32)

1.6 Eye drops 13 1038 34% -0.12 (-0.28 to 0.04) 34% -0.10 (-0.22 to 0.03)

1.7 Combinedsymptom-medi-cation scores

3 351 59% -0.21 (-0.55 to 0.13) 59% -0.21 (-0.42 to 0.00)

1.8 Conjunctivalimmediate aller-gen sensitivity

4 250 43% 0.35 (0.00 to 0.69) 43% 0.30 (0.05 to 0.55)

D I S C U S S I O N

The present systematic review demonstrates that SLIT is effectivein reducing ocular symptoms in people with AC with or withoutrhinitis. Even though early trials evaluating the effects of specificimmunotherapy did not particularly focus on symptoms of con-junctivitis, more recent studies have pointed out the improvementin ocular signs and symptoms when these have been evaluated asa separate outcome.

Randomised, double-masked placebo controlled trials evaluatingthe efficacy of subcutaneous immunotherapy have shown signifi-cant reductions in conjunctival symptoms in individuals with sea-sonal ARC (Calderon 2007). The study conducted by Dolz et alassessed the efficacy of a grass pollen allergen extract in participantswith SAR. After three continuous years of treatment, those pa-tients who received the injective immunotherapy presented lowerconjunctival scores compared with those participants receivingplacebo (P < 0.001). Moreover, the concentration of antigen nec-essary to make the test positive increased by 250 BU/ml in thetreated group (P < 0.01), while no changes were seen in the placebogroup (Dolz 1996). Similar figures were observed by Frew 2006in a comparison of an extract of Phleum pratense, standardised inSQ units, versus placebo in 410 participants with SAR. Across thewhole pollen season, ocular symptom scores were reduced in 30%

and 37% in the 10,000 (P = 0.0019) and 100,000 SQ-U (P <0.0001) groups, respectively, compared with those in the placebogroup. These findings were summarised in the meta-analysis byCalderon et al, evaluating both nasal and conjunctival outcomesin people with SAR treated with subcutaneous immunotherapy(Calderon 2007).

Sublingual immunotherapy has emerged as an effective alterna-tive to subcutaneous immunotherapy. The indications are simi-lar and, where both treatments are available, patient preferencebecomes an important determinant of choice (Durham 2007b).Recently, a subsequent analysis of a large double-masked placebocontrolled trial of a sublingual grass allergen tablet investigatedthe effect of SLIT on individual eye and nasal symptoms (Dahl2006b; Durham 2007). Six hundred and thirty-four participantswith rhinoconjunctivitis due to grass pollen were randomised 1:1to receive SLIT (n = 316) or placebo (n = 318) for at least 16 weeksprior to and continued during the grass pollen season. Consistentand highly significant reductions in individual eye and nasal symp-toms (from 22% to 44%) were observed following treatment withSLIT compared with placebo. For eye symptoms, the score forthe actively treated group was reduced in 36% as compared withplacebo (P < 0.0001). A separation of the eye symptoms into indi-vidual symptoms also showed consistently lower symptom scoresin the immunotherapy group. The percentage reductions relativeto placebo were -32% for gritty eyes (P < 0.0001) and 44% forwatery eyes (P < 0.0001) (Durham 2007). Motivated by these sta-



tistically significant results, we decided to carry out the currentreview.

This systematic review identified 54 randomised double-maskedplacebo controlled trials meeting the inclusion criteria. After a de-tailed evaluation of the papers and having made requests to theauthors for unpublished data, 40 of these trials were includedin the meta-analysis. Two studies (Torres-Lima 2002; Wuthrich2003) were included in the systematic review but not meta-anal-ysed as the raw data provided were not comparable with the pooleddata. Forty-one studies evaluated the ocular symptoms in patientswith rhinoconjunctivitis and one study was designed specificallyto assess the effect of SLIT in allergic perennial conjunctivitis(Mortemousque 2003).

The current systematic review and meta-analysis confirms thatSLIT significantly reduces both the total (SMD -0.41; P <0.00001) and individual ocular symptom scores for red eyes (SMD-0.34; P < 0.00001), itchy eyes (SMD -0.31; P < 0.00001) and wa-tery eyes (SMD -0.23; P = 0.0001) in patients with rhinoconjunc-tivitis. These observed effect sizes for SLIT over placebo comparefavourably with those observed in recent large, randomised, dou-ble-masked placebo controlled trials (Dahl 2006b; Didier 2007).These reductions were evident when the studies assessed seasonalallergens (SMD -0.38; 95% CI -0.50 to -0.25; P < 0.00001) butnot perennial (SMD -0.52; 95% CI -1.05 to 0.01; P = 0.05). Thesedifferences could be explained by the paucity of studies evaluatingperennial allergens (n = 6) and the small numbers of participantsanalysed for this outcome (SLIT 109 versus placebo 110) (Analysis1.9).

When the combined symptom medication scores were evaluated, amarginal, non-significant reduction in SMD was evident, but onlythree studies assessing 351 participants were included (Analysis1.8).

Sublingual immunotherapy in children induced a significant re-duction in the primary outcome after pooling the nine studies thatexclusively included participants aged four to 17 years. The SMDfor total ocular symptom scores was -0.27 (95% CI -0.46 to -0.07;P = 0.007; I2 = 39%) favouring SLIT. Recent studies in children,including large populations, have shown a significant reductionin total ocular symptom scores in those patients receiving SLIT(Bufe 2008; Wahn 2009). The SMD for symptom reductions inadults was -0.48 (95% CI -0.63 to -0.32; P < 0.00001; I2 = 64%)(Analysis 1.10).

Increasing the duration of treatment beyond 12 months did notaffect the treatment effect (# 12 months: SMD -0.43; P < 0.0001;I2 = 58%, and > 12 months: SMD -0.43; P < 0.01; I2 = 68%).However, this subgroup analysis is difficult to assess due to thefact that most of the studies evaluated diverse schedules of treat-ment, different types of allergens, and the timing of treatment wasvariable with respect to pollen seasons. Other factors such as the

frequency of administration of the SLIT and the continuity of thetreatment out of season may also affect outcomes (Analysis 1.12).

Previous meta-analyses have demonstrated reductions in medica-tion scores in people receiving SLIT (Penagos 2006; Penagos 2008;Wilson 2005). The participants in large studies also used signif-icantly less rescue medication compared with the placebo group(reduction of total symptom score 38%; P < 0.0001) (Dahl 2006b;Didier 2007). In the current review, we did not find a significanteffect of SLIT in the reduction of eye drops use (SMD -0.12; 95%CI -0.28 to 0.04; P = 0.14; I2 = 34%). This lack of effect could beexplained by the fact that participants generally are instructed touse intranasal steroids and take systemic antihistamines as rescuemedications. These medications are easy to take and both havebeen demonstrated to be effective in reducing ocular symptomsin patients with ARC. In a recent retrospective pooled analysis offour RCTs of patients with SAR, mometasone furoate nasal spray200 µg once daily proved to be effective in reducing morningand evening total ocular symptom scores and the individual ocu-lar symptom scores compared with placebo (Bielory 2008b). An-other retrospective analysis of four RCTs, evaluating the efficacyof fluticasone furoate nasal spray (FFNS) in patients with ARC,provided evidence of significant reductions in the reflective totalocular symptom scores in those patients treated with FFNS com-pared with placebo (Scadding 2008). The mechanism by whichan intranasal corticosteroid reduces ocular allergic symptoms hasbeen under investigation and some effects on both the reflex neuralactivity and the local inflammation, facilitating the nasolacrimaldrainage, have been proposed (Bielory 2007b; Bielory 2008b).Baroody 2009 conducted a double-masked, placebo controlledrandomised, crossover experiment in 20 people with seasonal AR.A localised and unilateral nasal challenge with grass or ragweedextracts was performed consecutively for three days after one weekof treatment with either placebo or FFNS. A nasal challenge led tosneezing and a nasonasal reflex, which increased after three repeti-tive antigen challenges, demonstrating priming. Ocular symptomsalso increased after each nasal challenge with antigen, supportingthe existence of a nasal-ocular reflex response and its ability toprime in response to nasal inflammation. Treatment with FFNSreduced sneezing, the nasonasal and nasal-ocular reflexes, ocularsymptoms and the amount of eosinophils in nasal secretions. Theauthors postulated that reductions in both allergic inflammationand the nasal-ocular reflex provide a potential mechanism to ex-plain how treatment with an intranasal steroid may work locally inthe nose to reduce the ocular symptoms associated with AR. Ad-ditionally, antihistamines such as desloratadine and levocetirizinehave shown reductions in individual ocular symptoms followingallergen conjunctival challenges or continuous treatment for AR,respectively (Canonica 2008; Torkildsen 2009).

Regarding the allergen dose, available evidence especially that de-rived from large comparisons evaluating diverse dosages of pollenextracts has demonstrated that the efficacy is related to the daily



amount of allergen administered (Dahl 2006b; Didier 2007;Durham 2006; Valovirta 2006). Meta-analyses are not the bestmethods to determine the effect of the allergen dose on the clini-cal outcomes. This is due to the diversity of allergen preparationsused, variable daily and cumulative doses, and the lack of infor-mation in some studies regarding the dose of the major allergenexpressed in a common unit (µg). According to The CochraneCollaboration, other statistical methods are available to assess thisrelationship, such as meta-regression. However, the ideal way oflooking at the effect of dose would be to have randomised tri-als comparing the doses (head-to-head comparisons) (Calderon2008; Higgins 2011a).

The risk of severe systemic reactions, including anaphylaxis, hasbeen a key concern in relation to SLIT. Encouragingly, no treat-ment-related severe systemic adverse events requiring interventionwith adrenaline has occurred during diverse large-scale randomisedmulticentre trials using SLIT (Durham 2008; Radulovic 2007b).Even though our analysis was not designed to assess safety, the ex-amined trials consistently described the large majority of adverseeffects as mild and self-resolving, in accordance with previous re-views.

We identified some studies with design limitations, lack of samplesize calculations and poor measures to prevent bias. These studies,basically published earlier, did not follow the Consolidated Stan-dards of Reporting Trials (CONSORT) statement for the pub-lication of RCTs. This made the identification of key informa-tion regarding randomisation methods and concealment of allo-cation difficult. On the other hand, publication bias is an impor-tant drawback of systematic reviews and it is difficult to avoid.Although we searched for articles in the most important electronicdatabases of medical information, in abstract books from relevantmeetings and in the most diffuse languages, it is possible thatnot all the studies have been found. The analyses of publicationbias for total ocular symptom scores using the funnel plot analy-sis and the Egger’s test did not show a statistical significant bias.However, significant bias was detected using the Begg’s test. Werecognise that these findings are inconclusive in relation to thepossibility of publication bias and that there is a risk of selectivereporting in some studies and the GRADE score has thereforebeen downgraded accordingly (Summary of findings for the maincomparison). We encourage authors to publish ’negative resultsstudies’ to allow researchers to avoid publication bias.

We identified some possible sources of bias in the present meta-analysis as some outcomes presented a degree of inter-study incon-sistency (heterogeneity); studies with low statistical power wereincluded; and some outcomes included small numbers of studies(Higgins 2011a). Heterogeneity between studies was significantin this review, resulting largely from methodological and clinicalheterogeneity (that is differences in scoring systems; sample sizes;type, schedule and dose of allergen; age groups; treatment du-ration; disease severity) across studies. As a consequence, we de-

creased the quality of evidence according to GRADE (Summaryof findings for the main comparison). Moreover, we recognise thefact that data were skewed in relation to a number of studies thatwere included in this review and we therefore suggest that thefindings from our meta-analyses be interpreted with caution.

This review has several strengths, such as the restrictive inclusioncriteria for the studies, the statistically significant effect size foundaccording to Cohen’s criteria, the robust statistical methods tocontrol both inter- and intra-study variability and the quantitativeapproach carried out. Moreover, most of the analysed data wereprovided by the authors.

We need more well-designed and powered studies assessing theimpact on quality of life and cost-effectiveness and head-to-headstudies with other treatment regimens. We identified 14 ran-domised, parallel-group, double-masked and placebo controlledclinical trials in an international clinical trials registry (http://clinicaltrials.gov/) which are currently in progress. Their data werenot available for inclusion in this review. A better understandingof the long-term effectiveness of SLIT in inducing tolerance is alsorequired.

In conclusion, SLIT has effects on multiple allergic symptoms,including ocular symptoms, and is effective in the treatment ofrhinoconjunctivitis.

Summary of main results

This comprehensive review identified 811 studies from whichonly 42 trials were included in the analysis. The current evidencesuggests beneficial effects of specific allergen immunotherapy inreducing ocular symptoms in people with allergic conjunctivitis(AC) with or without rhinitis. Heterogeneity among studies (I2

statistic) was around 50% or below for all endpoints. Sublingualimmunotherapy significantly reduced both total ocular symptomscores and individual ocular symptoms scores (redness, itchinessand watery eyes) compared to placebo. The pooled estimates sug-gested, however, that SLIT is likely to have a small to moderateeffect in AC-related ocular symptoms.

Overall completeness and applicability ofevidence

The 42 included studies enrolled over 3958 participants with AC.The participants in all the included trials were selected based onobjective confirmation of their atopic status and the clinical man-ifestation of the allergic disease. Most of the studies reported ade-quately on the age and sex of the participants, the allergen causingdisease and disease severity. Therefore the participants were repre-sentative of patients with AC, which enhances the generalisabilityof our findings.

Quality of the evidence



http://clinicaltrials.gov/



All trials in this review had the same study design and we includedthose studies evaluating the same clinical outcomes. The distribu-tion of participants between the therapeutic intervention, receiv-ing SLIT (n = 2011), and placebo (n = 1947) was well-propor-tioned. Heterogeneity among studies (I2 statistic) was around 50%or below for all endpoints. This applies for all outcomes exceptfor swollen eyes (I2 = 83%); however this outcome was assessedin only two studies. Subgroup analysis for total ocular symptomscores did not decrease statistical heterogeneity, therefore we can-not rule out that the moderate heterogeneity observed for this out-come is due to a true variability of effects in the studies, or dueto methodological variability (for example the measurement toolsused to obtain the total symptom score).A key methodological limitation is the small sample size of mostof the studies (56% had less than 30 participants per arm). In thisreview, only 17% included more than 100 participants in eacharm, 8% up to 50 and 19% up to 30 participants. Some trialsdid not adequately describe their method of randomisation orallocation concealment thus precluding formal assessment of thelikelihood of selection bias.

Potential biases in the review process

By using the Cochrane risk of bias tool we identified that only50% of the included trials reported an adequate sequence genera-tion; 90% described the methods to mask the interventions; 95%addressed incomplete outcome data; 95% were considered free ofselective reporting and 79% were free of other bias. It is importantto mention that only 29% of the studies provided a descriptionof the allocation concealment methods. Due to the nature of thedisease, the majority of the studies aimed to treat rhinoconjunc-tivitis and not the ocular component by itself; only one study wasspecifically designed to evaluate just conjunctivitis. However, inall the studies eye symptom scores were planned to be assessed asa primary or secondary endpoint.Limitations of this review are moderate heterogeneity and poten-tial publication bias. Finally, the clinical relevance of the benefitregarding the primary outcome ’total symptom score’ is not intu-itive, given the use of SMD in our review. Based on a common ruleof thumb, also mentioned in the Cochrane Handbook for SystematicReviews of Interventions (Patrick 2008), for our primary outcomethe observed effect size (SMD -0.41; 95% CI - 0.53 to - 0.28)ranges between a small and moderate benefit.

Agreements and disagreements with otherstudies or reviews

To our knowledge, this is the first systematic review on this topic;

therefore, comparisons with other reviews cannot be made.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

This rigorously conducted review of a substantive body of trialevidence has found that SLIT is overall effective in reducing ocu-lar symptoms in people with ARC. Clinical interpretation of theeffectiveness of SLIT in reducing symptoms, which was expressedas the standardised mean difference, can be difficult, but is com-parable to that observed in previous Cochrane reviews of SLIT fornasal symptoms. The overall quality of the evidence was assessedto be low to moderate due in part to limitations with the descrip-tion of allocation concealment in some studies, moderate statisti-cal heterogeneity and possible publication bias. In summary, thisreview provides evidence that once daily treatment with SLIT inthe form of either drops or sublingual tablets represents a treat-ment option in patients with AC and ARC with ocular symptoms.

Implications for research

Further large ‘definitive’ trials are required as well as head-to-headcomparative studies with currently available anti-allergic drugs.Whether SLIT may result in long-term benefits after discontin-uation of therapy is an important question that warrants furtherevaluation. There is a paucity of pharmaco-economic evaluationsand such studies are also necessary to help clarify the place of SLITin comparison with other treatment options. Further studies eval-uating the mechanisms of SLIT are needed. There is also a need todevelop and validate standard instruments, such as questionnaireswith adequate psychometrical properties, in this field of research,which would also make future studies more comparable and ade-quate for meta-analysis.

A C K N O W L E D G E M E N T S

We thank Anupa Shah, Managing Editor for the Cochrane Eyesand Vision Group (CEVG) for all her support. We acknowledgethe CEVG Trials Search Co-ordinator, Iris Gordon, for devisingand running the electronic searches. We thank the Co-ordinatingEditor, Richard Wormald, for his assistance and comments. We aregrateful to Dr Gianni Virgili for his invaluable statistical support.We thank Leonard Bielory and Catey Bunce for their commentson the review. We are thankful to Dr Chen Ji and Dr Guo Yifengfor their help in translating the paper published in Chinese.



R E F E R E N C E S

References to studies included in this review

Andre 2003 {published and unpublished data}André C, Perrin-Fayolle M, Grosclaude M, CouturierP, Basset D, Cornillon J, et al.A double-blind placebo-controlled evaluation of sublingual immunotherapy witha standardized ragweed extract in patients with seasonalrhinitis. Evidence for a dose-response relationship.International Archives of Allergy and Immunology 2003;131(2):111–8.

Ariano 2001 {published and unpublished data}Ariano R, Spadolini I, Panzani RC. Efficacy of sublingualspecific immunotherapy in Cupressaceae allergy usingan extract of Cupressus arizonica. A double blind study.Allergologia et Immunopathologia 2001;29(6):238–44.

Aydogan 2007 {published and unpublished data}Aydogan M, Keles S, Eifan A, Akkoc T, Yildiz A, Gursoy M,et al.Impact of sublingual immunotherapy on developmentof asthma in children with allergic rhinitis sensitised tohouse-dust-mite: a double blind placebo controlled study.Allergy 2007;62:74.

Bowen 2004 {published data only}Bowen T, Greenbaum J, Charbonneau Y, Hebert J,Filderman R, Sussman G, et al.Canadian trial of sublingualswallow immunotherapy for ragweed rhinoconjunctivitis.Annals of Allergy, Asthma & Immunology 2004;93(5):425–30.

Bufe 2004 {published and unpublished data}

Bufe A, Ziegler-Kirbach E, Stoeckmann E, Heidemann P,Gehlhar K, Holland-Letz T, et al.Efficacy of sublingualswallow immunotherapy in children with severe grass pollenallergic symptoms: a double-blind placebo-controlled study.Allergy 2004;59(5):498–504.

Bufe 2008 {unpublished data only}Bufe A, Eberle P, Franke-Beckmann E, Funck J, Klimek L,Stephan V, et al.Phase III trial with grass allergen tablet forsublingual Immunotherapy in children. Journal of Allergyand Clinical Immunology 2008;121 Suppl 1(2):127.

Cao 2007 {published and unpublished data}

Cao LF, Lu Q, Gu HL, Chen YP, Zhang Y, Lu M, etal.Clinical evaluation for sublingual immunotherapy ofallergic asthma and atopic rhinitis with dermatophagoidesfarinae drops. Zhonghua Er Ke Za Zhi 2007;45(10):736–41.

Casanovas 1994 {published and unpublished data}Casanovas M, Guerra F, Moreno C, Miguel R, Marañón F,Daza JC. Double-blind, placebo-controlled clinical trialof preseasonal treatment with allergenic extracts of Oleaeuropaea pollen administered sublingually. Journal ofInvestigational Allergology & Clinical Immunology 1994;4(6):305–14.

Dahl 2006a {published and unpublished data}

Dahl R, Stender A, Rak S. Specific immunotherapy withSQ standardized grass allergen tablets in asthmatics withrhinoconjunctivitis. Allergy 2006;61(2):185–90.

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de Blay 2007 {published and unpublished data}de Blay F, Barnig C, Kanny G, Purohit A, Leynadier F,Tunon de Lara JM, et al. SUBLIM Group. Sublingual-swallow immunotherapy with standardized 3-grass pollenextract: a double-blind, placebo-controlled study. Annals ofAllergy, Asthma & Immunology 2007;99(5):453–61.

Didier 2007 {published and unpublished data}Didier A, Malling HJ, Worm M, Horak F, Jäger S,Montagut A, et al.Optimal dose, efficacy, and safety ofonce-daily sublingual immunotherapy with a 5-grass pollentablet for seasonal allergic rhinitis. Journal of Allergy andClinical Immunology 2007;120(6):1338–45.

Dubakiene 2003 {unpublished data only}Dubakiene R, Kleinjans HAJ. Effectiveness of SpecificSublingual IT (SLIT) with tree pollen. A placebo controlledstudy in 119 patients. XXII Congress of the EuropeanAcademy of Allergy and Clinical Immunology. Paris,France. 2003:Abstract No. 785.

Durham 2006 {published and unpublished data}

Durham SR, Yang WH, Pedersen MR, Johansen N,Rak S. Sublingual immunotherapy with once-daily grassallergen tablets: a randomized controlled trial in seasonalallergic rhinoconjunctivitis. Journal of Allergy and ClinicalImmunology 2006;117(4):802–9.

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Hirsch 1997 {published and unpublished data}

Hirsch T, Sähn M, Leupold W. Double-blind placebo-controlled study of sublingual immunotherapy with housedust mite extract (D.pt.) in children. Pediatric Allergy andImmunology 1997;8(1):21–7.

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Khinchi 2004 {published and unpublished data}

Khinchi MS, Poulsen LK, Carat F, André C, HansenAB, Malling HJ. Clinical efficacy of sublingual andsubcutaneous birch pollen allergen-specific immunotherapy:a randomized, placebo-controlled, double-blind, double-dummy study. Allergy 2004;59(1):45–53.



La Rosa 1999 {published and unpublished data}

La Rosa M, Ranno C, André C, Carat F, Tosca MA,Canonica GW. Double-blind placebo-controlled evaluationof sublingual-swallow immunotherapy with standardizedParietaria judaica extract in children with allergicrhinoconjunctivitis. Journal of Allergy and ClinicalImmunology 1999;104(2 Pt 1):425–32.

Moreno-Ancillo 2007 {published and unpublished data}

Moreno-Ancillo A, Moreno C, Ojeda P, Domínguez C,Barasona MJ, García-Cubillana A, et al.Efficacy and qualityof life with once-daily sublingual immunotherapy withgrasses plus olive pollen extract without updosing. Journalof Investigational Allergology & Clinical Immunology 2007;17(6):399–405.

Mortemousque 2003 {published and unpublished data}

Mortemousque B, Bertel F, De Casamayor J, Verin P, ColinJ. House-dust mite sublingual-swallow immunotherapy inperennial conjunctivitis: a double-blind, placebo-controlledstudy. Clinical and Experimental Allergy 2003;33(4):464–9.

Ott 2008 {published data only}

Ott H, Sieber J, Brehler R, Fölster-Holst R, Kapp A, KlimekL, et al.Efficacy of grass pollen sublingual immunotherapyfor three consecutive seasons and after cessation oftreatment: the ECRIT study. Allergy 2009;64(9):179–86.

Palma-Carlos 2006 {published and unpublished data}Palma-Carlos AG, Santos AS, Branco-Ferreira M, PregalAL, Palma-Carlos ML, Bruno ME, et al.Clinical efficacyand safety of preseasonal sublingual immunotherapy withgrass pollen carbamylated allergoid in rhinitic patients.A double-blind, placebo-controlled study. Allergologia etImmunopathologia 2006;34(5):194–8.

Panzner 2008 {published data only}Panzner P, Petrás M, S!kora T, Lesná I. Double-blind,placebo-controlled evaluation of grass pollen specificimmunotherapy with oral drops administered sublinguallyor supralingually. Respiratory Medicine 2008;102(9):1296–1304.

Passalacqua 1998 {published data only}Passalacqua G, Albano M, Fregonese L, Riccio A, PronzatoC, Mela GS, et al.Randomised controlled trial of localallergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis. Lancet 1998;351(9103):629–32.

Passalacqua 1999 {published data only}Passalacqua G, Albano M, Riccio A, Fregonese L, PuccinelliP, Parmiani S, et al.Clinical and immunologic effects of arush sublingual immunotherapy to Parietaria species: Adouble-blind, placebo-controlled trial. Journal of Allergyand Clinical Immunology 1999;104(5):964–8.

Passalacqua 2006 {published data only}

Passalacqua G, Pasquali M, Ariano R, Lombardi C,Giardini A, Baiardini I, et al.Randomized double-blindcontrolled study with sublingual carbamylated allergoidimmunotherapy in mild rhinitis due to mites. Allergy 2006;61(7):849–54.

Pfaar 2008 {published and unpublished data}

Pfaar O, Klimek L. Efficacy and safety of specificimmunotherapy with a high-dose sublingual grass pollenpreparation: a double-blind, placebo-controlled trial.Annals of Allergy, Asthma & Immunology 2008;100(3):256–63.

Pradalier 1999 {published and unpublished data}

Pradalier A, Basset D, Claudel A, Couturier P, WesselF, Galvain S, et al.Sublingual-swallow immunotherapy(SLIT) with a standardized five-grass-pollen extract (dropsand sublingual tablets) versus placebo in seasonal rhinitis.Allergy 1999;54(8):819–28.

Purello-D’ Ambrosio 1999 {published and unpublished data}

Purello-D’Ambrosio F, Gangemi S, Isola S, La Motta N,Puccinelli P, Parmiani S, et al.Sublingual immunotherapy:a double-blind, placebo-controlled trial with Parietariajudaica extract standardized in mass units in patients withrhinoconjunctivitis, asthma, or both. Allergy 1999;54(9):968–73.

Rolinck-Werninghaus 2004 {published and unpublished data}Rolinck-Werninghaus C, Wolf H, Liebke C, Baars JC,Lange J, Kopp MV, et al.A prospective, randomized,double-blind, placebo-controlled multi-centre study on theefficacy and safety of sublingual immunotherapy (SLIT) inchildren with seasonal allergic rhinoconjunctivitis to grasspollen. Allergy 2004;59(12):1285–93.

Röder 2007 {published and unpublished data}Röder E, Berger MY, Hop WC, Bernsen RM, de Groot H,Gerth van Wijk R. Sublingual immunotherapy with grasspollen is not effective in symptomatic youngsters in primarycare. Journal of Allergy and Clinical Immunology 2007;119(4):892–8.

Sanchez-Palacios 2001 {published and unpublished data}Sánchez Palacios A, Schamann F, García JA. Sublingualimmunotherapy with cat epithelial extract. Personalexperience. Allergologia et Immunopathologia 2001;29(2):60–5.

Smith 2004 {published and unpublished data}

Smith H, White P, Annila I, Poole J, Andre C, FrewA. Randomized controlled trial of high-dose sublingualimmunotherapy to treat seasonal allergic rhinitis. Journal ofAllergy and Clinical Immunology 2004;114(4):831–7.

Torres-Lima 2002 {published and unpublished data}Torres-Lima M, Wilson D, Pitkin L, Roberts A, Nouri-Aria K, Jacobson M, et al.Grass pollen sublingualimmunotherapy for seasonal rhinoconjunctivitis: arandomized controlled trial. Clinical and ExperimentalAllergy 2002;32(4):507–14.

Troise 1995 {published and unpublished data}

Troise C, Voltolini S, Canessa A, Pecora S, Negrini AC.Sublingual immunotherapy in Parietaria pollen-inducedrhinitis: a double-blind study. Journal of InvestigationalAllergology & Clinical Immunology 1995;5(1):25–30.

Valovirta 2006 {published data only}Valovirta E, Jacobsen L, Ljørring C, Koivikko A, SavolainenJ. Clinical efficacy and safety of sublingual immunotherapy



with tree pollen extract in children. Allergy 2006;61(10):1177–83.

Vervloet 2007 {published and unpublished data}

Vervloet D, Birnbaum J, Laurent P, Hugues B, Fardeau MF,Massabie-Bouchat YP, et al.Safety and efficacy of Juniperusashei sublingual-swallow ultra-rush pollen immunotherapyin cypress rhinoconjunctivitis. A double-blind, placebo-controlled study. International Archives of Allergy andImmunology 2007;142(3):239–46.

Voltolini 2001 {published data only}Voltolini S, Modena P, Minale P, Bignardi D, Troise C,Puccinelli P, et al.Sublingual immunotherapy in tree pollenallergy. Double-blind, placebo-controlled study with abiologically standardised extract of three pollens (alder, birchand hazel) administered by a rush schedule. Allergologia etImmunopathologia 2001;29(4):103–10.

Vourdas 1998 {unpublished data only}Vourdas D, Syrigou E, Potamianou P, Carat F, Batard T,André C, et al.Double-blind, placebo-controlled evaluationof sublingual immunotherapy with standardized olive pollenextract in pediatric patients with allergic rhinoconjunctivitisand mild asthma due to olive pollen sensitization. Allergy1998;53(7):662–72.

Wahn 2009 {published and unpublished data}

Wahn U, Tabar A, Kuna P, Halken S, Montagut A, deBeaumont O, et al. SLIT Study Group. Efficacy and safetyof 5-grass-pollen sublingual immunotherapy tablets inpediatric allergic rhinoconjunctivitis. Journal of Allergy andClinical Immunology 2009;123(1):160–6.

Wuthrich 2003 {published data only}Wüthrich B, Bucher Ch, Jörg W, Bircher A, Eng P,Schneider Y, et al.Double-blind, placebo-controlled studywith sublingual immunotherapy in children with seasonalallergic rhinitis to grass pollen. Journal of InvestigationalAllergology & Clinical Immunology 2003;13(3):145–8.

References to studies excluded from this review

Alvarez-Cuesta 2007 {published and unpublished data}

Alvarez-Cuesta E, Berges-Gimeno P, González-ManceboE, Fernández-Caldas E, Cuesta-Herranz J, Casanovas M.Sublingual immunotherapy with a standardized cat danderextract: evaluation of efficacy in a double blind placebocontrolled study. Allergy 2007;62(7):810–7.

Amar 2009 {published data only}Amar SM, Harbeck RJ, Sills M, Silveira LJ, O’Brien H,Nelson HS. Response to sublingual immunotherapy withgrass pollen extract: monotherapy versus combinationin a multiallergen extract. Journal of Allergy and ClinicalImmunology 2009;124(1):150–6.

Bahceciler 2001 {published data only}Bahçeciler NN, Isik U, Barlan IB, Basaran MM. Efficacyof sublingual immunotherapy in children with asthma andrhinitis: a double-blind, placebo-controlled study. PediatricPulmonology 2001;32(1):49–55.

Bahceciler 2005 {published data only}

Bahceciler NN, Arikan C, Taylor A, Akdis M, Blaser K,Barlan IB, et al.Impact of sublingual immunotherapy onspecific antibody levels in asthmatic children allergic tohouse dust mites. International Archives of Allergy andImmunology 2005;136(3):287–94.

Boquete 2006 {published and unpublished data}

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Bordignon 2003 {published data only}

Bordignon V, Parmiani S. Variation of the skin end-pointin patients treated with sublingual specific immunotherapy.Journal of Investigational Allergology & Clinical Immunology2003;13(3):170–6.

Brown 2001 {published data only}

Brown JL, Frew AJ. The efficacy of oromucosalimmunotherapy in respiratory allergy. Clinical andExperimental Allergy 2001;31(1):8–10.

Burastero 2008 {published data only}

Burastero S, Falangiani P, Paolucci C, Breda D, RoncaroloD, Zanotta S, et al.Clinical and immunological correlatesof pre-co-seasonal sublingual immunotherapy withbirch monomeric allergoid in patients with allergicrhinoconjunctivitis. Allergy 2008;63 Suppl 88:227.

Caffarelli 2000 {published data only}Caffarelli C, Sensi LG, Marcucci F, Cavagni G. Preseasonallocal allergoid immunotherapy to grass pollen in children: adouble-blind, placebo-controlled, randomized trial. Allergy2000;55(12):1142–7.

Ciprandi 2007 {published data only}

Ciprandi G, Alesina R, Ariano R, Borreli P, CadarioG, Capristo A, et al.Sublingual immunotherapy inpolysensitized patients: a preliminary study. Allergy 2007;62 Suppl 83:241.

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Clavel 1998 {published data only}

Clavel R, Bousquet J, André C. Clinical efficacy ofsublingual-swallow immunotherapy: a double-blind,placebo-controlled trial of a standardized five-grass-pollenextract in rhinitis. Allergy 1998;53(5):493–8.

Di Rienzo 2006 {published data only}

Di Rienzo V, Pucci S, D’Alo S, Di Cara G, Incorvaia C,Frati F, et al.Effects of high-dose sublingual immunotherapyon quality of life in patients with cypress-induced rhinitis: Aplacebo-controlled study. Clinical and Experimental AllergyReviews 2006;6(3):67–70.



Didier 2009 {published data only}

Didier A, Melac M, Montagut A, Lhéritier-Barrand M,Tabar A, Worm M. Agreement of efficacy assessments forfive-grass pollen sublingual tablet immunotherapy. Allergy2009;64(1):166–71.

Drachenberg 2001 {published data only}Drachenberg KJ, Pfeiffer P, Urban E. Sublingualimmunotherapy - Results from a a multi-centre,randomised, double-blind, placebo-controlled study withstandardised birch and grass/rye pollen extract. Allergologie2001;24(11):525–34.

Durham 2007 {published data only}

Durham SR, Riis B. Grass allergen tablet immunotherapyrelieves individual seasonal eye and nasal symptoms,including nasal blockage. Allergy 2007;62(8):954–7.

Durham 2010 {published data only}Durham SR, Emminger W, Kapp A, Colombo G, deMonchy JG, Rak S, et al.Long-term clinical efficacy in grasspollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet. Journal ofAllergy and Clinical Immunology 2010;125(1):131–8.

Esch 2008 {unpublished data only}Esch RE, Bush RK, Skoner D, Gentile D, McLaughlin A,Fasano MB. Parallel, randomized, double-blind, placebo-controlled, dose-response phase IIb trial in adults for shortragweed sublingual-oral immunotherapy (SLIT). Journal ofAllergy and Clinical Immunology 2008;121 Suppl 1(2):127.

Grosclaude 2002 {published data only}

Grosclaude M, Bouillot P, Alt R, Leynadier F, ScheinmannP, Rufin P, et al.Safety of various dosage regimens duringinduction of sublingual immunotherapy: A preliminarystudy. International Archives of Allergy and Immunology2002;129(3):248–53.

Guez 2000 {published data only}Guez S, Vatrinet C, Fadel R, André C. House-dust-mitesublingual-swallow immunotherapy (SLIT) in perennialrhinitis: a double-blind, placebo-controlled study. Allergy2000;55(4):369–75.

Horak 2008 {published data only}

Horak F, Siegfried J, Worm M, Melac M, Didier A.Clinical efficacy of sublingual immunotherapy (SLIT) withgrass pollen tablets in patients with rhinoconjunctivitisthroughout the pollen season and at peak pollen. Allergy2008;63 Suppl 88:226.

Horak 2009 {published data only}

Horak F, Jaeger S, Worm M, Melac M, Didier A.Implementation of pre-seasonal sublingual immunotherapywith a five-grass pollen tablet during optimal dosageassessment. Clinical and Experimental Allergy 2009;39(3):394–400.

Horak 2009a {published data only}

Horak F, Zieglmayer P, Zieglmayer R, Lemell P, Devillier P,Montagut A, et al.Early onset of action of a 5-grass-pollen300-IR sublingual immunotherapy tablet evaluated in anallergen challenge chamber. Journal of Allergy and ClinicalImmunology 2009;124(3):471–7.

Hordijk 1998 {published data only}

Hordijk GJ, Antvelink JB, Luwema RA. Sublingualimmunotherapy with a standardised grass pollen extract;a double-blind placebo-controlled study. Allergologia etImmunopathologia 1998;26(5):234–40.

Horiguchi 2008a {published data only}Horiguchi S, Okamoto Y, Yonekura S, Okawa T, YamamotoH, Kunii N, et al.A randomized controlled trial of sublingualimmunotherapy for Japanese cedar pollinosis. InternationalArchives of Allergy and Immunology 2008;146(1):76–84.

Horiguchi 2008b {published data only}Horiguchi S, Okamoto Y, Yonekura S, Okawa T, Kunii N,Yamamoto H, et al.Lowered effectiveness of immunotherapyfor cypress pollinosis by using Japanese cedar pollen extract.Arerugi 2008;57(5):558–61.

Ippoliti 2003 {published data only}

Ippoliti F, De Santis W, Volterrani A, Lenti L, Canitano N,Lucarelli S, et al.Immunomodulation during sublingualtherapy in allergic children. Pediatric Allergy andImmunology 2003;14(3):216–21.

Kleine-Tebbe 2007 {published data only}Kleine-Tebbe J, Bachert C, Bergmann KC, Bieber T,Brehler R, Friedrichs F, et al.Present role of sublingualimmunotherapy in allergic diseases. Allergologie 2007;30:378–88.

Lombardi 2005 {published data only}Lombardi C, Passalacqua G, Ariano R, Pasquali M, BaiardiniI, Giardini A, et al.A 3-year randomized controlled studywith sublingual immunotherapy in mite-induced respiratoryallergy. Journal of Allergy and Clinical Immunology 2005;115 Suppl 2:207.

Lue 2006 {published data only}

Lue KH, Lin YH, Sun HL, Lu KH, Hsieh JC, ChouMC. Clinical and immunologic effects of sublingualimmunotherapy in asthmatic children sensitized to mites:a double-blind, randomized, placebo-controlled study.Pediatric Allergy and Immunology 2006;17(6):408–15.

Maestrelli 2004 {published data only}

Maestrelli P, Zanolla L, Pozzan M, Fabbri LM. Effect ofspecific immunotherapy added to pharmacologic treatmentand allergen avoidance in asthmatic patients allergic tohouse dust mite. Journal of Allergy and Clinical Immunology2004;113(4):643–9.

Malling 2009 {published data only}

Malling HJ, Montagut A, Melac M, Patriarca G, PanznerP, Seberova E, et al.Efficacy and safety of 5-grass pollensublingual immunotherapy tablets in patients with differentclinical profiles of allergic rhinoconjunctivitis. Clinical andExperimental Allergy 2009;39(3):387–93.

Marcucci 2001 {published data only}

Marcucci F, Sensi L, Frati F, Senna GE, Canonica GW,Parmiani S, et al.Sublingual tryptase and ECP in childrentreated with grass pollen sublingual immunotherapy (SLIT):safety and immunologic implications. Allergy 2001;56(11):1091–5.



Marcucci 2003 {published data only}

Marcucci F, Sensi L, Frati F, Bernardini R, Novembre E,Barbato A, et al.Effects on inflammation parameters of adouble-blind, placebo controlled one-year course of SLITin children monosensitized to mites. Allergy 2003;58(7):657–62.

Marcucci 2005a {published data only}Marcucci F, Sensi L, Di Cara G, Incorvaia C, Frati F.Dose dependence of immunological response to sublingualimmunotherapy. Allergy 2005;60(7):952–6.

Marcucci 2005b {published and unpublished data}Marcucci F, Sensi L, Di Cara G, Salvatori S, BerniniM, Pecora S, et al.Three-year follow-up of clinical andinflammation parameters in children monosensitized tomites undergoing sub-lingual immunotherapy. PediatricAllergy and Immunology 2005;16(6):519–26.

Maria 2004 {published data only}Maria D, Dervaderics M. Long-lasting effect of sublingualragweed immunotherapy: A 5 year prospective study.Journal of Allergy and Clinical Immunology 2004;113 Suppl

2:105.

Mitsch 1996 {published data only}Mitsch A, Drachenberg KJ. Positive results in a primarymulticentric study, specific immunotherapy administeredsublingually. TW Padiatrie 1996;9(11-12):628–31.

Mungan 1999 {published data only}Mungan D, Misirligil Z, Gürbüz L. Comparison of theefficacy of subcutaneous and sublingual immunotherapy inmite-sensitive patients with rhinitis and asthma--a placebocontrolled study. Annals of Allergy, Asthma & Immunology1999;82(5):485–90.

Mösges 2007 {published data only}

Mösges R, Brüning H, Hessler HJ, Götz G, KnaussmannHG. Sublingual immunotherapy in pollen-induced seasonalrhinitis and conjunctivitis: a randomized controlled trial.Acta Dermatovenerologica Alpina, Panonica, et Adriatica2007;16(4):143–8.

Nelson 1993 {published data only}

Nelson HS, Oppenheimer J, Vatsia GA, Buchmeier A. Adouble-blind, placebo-controlled evaluation of sublingualimmunotherapy with standardized cat extract. Journal ofAllergy and Clinical Immunology 1993;92(2):229–36.

Niu 2006 {published data only}Niu CK, Chen WY, Huang JL, Lue KH, Wang JY. Efficacyof sublingual immunotherapy with high-dose mite extractsin asthma: a multi-center, double-blind, randomized, andplacebo-controlled study in Taiwan. Respiratory Medicine2006;100(8):1374–83.

Okubo 2008 {published data only}Okubo K, Gotoh M, Fujieda S, Okano M, Yoshida H,Morikawa H, et al.A randomized double-blind comparativestudy of sublingual immunotherapy for cedar pollinosis.Allergology International 2008;57(3):265–75.

Pajno 2000 {published data only}Pajno GB, Morabito L, Barberio G, Parmiani S. Clinicaland immunologic effects of long-term sublingual

immunotherapy in asthmatic children sensitized to mites: adouble-blind, placebo-controlled study. Allergy 2000;55(9):842–9.

Pajno 2003 {published data only}Pajno GB, Vita D, Parmiani S, Caminiti L, La GruttaS, Barberio G. Impact of sublingual immunotherapy onseasonal asthma and skin reactivity in children allergic toParietaria pollen treated with inhaled fluticasone propionate.Clinical and Experimental Allergy 2003;33(12):1641–7.

Peter 2009 {published data only}Peter R, Kleinjans H, Hecker H. Significant increase inIgG4 levels after slit grass treatment. A double-blind,placebo-controlled, multi-center study (Twin GrassesStudy). Allergy 2009;64 Suppl 90:352–3.

Potter 2007 {unpublished data only}

Potter P, Nurse B, Hawarden D, Combebias A, Fadel R.Quality of life and symptoms assessment in sublingualimmunotherapy for patients with house-dust mite relatedperennial rhinitis: definition of a responder profile.World Allergy Organization Journal. XXth World AllergyOrganization Congress & VIIth Asia Pacific Congress ofAllergology, Asthma and Clinical Immunology, Bangkok,Thailand. 2007:S228.

Quirino 1996 {published data only}Quirino T, Iemoli E, Siciliani E, Parmiani S, Milazzo F.Sublingual versus injective immunotherapy in grass pollenallergic patients: a double blind (double dummy) study.Clinical and Experimental Allergy 1996;26(11):1253–61.

Radu 2007 {published data only}

Radu J, Du Buske L. Clinical efficacy and side effects ofsublingual immunotherapy vs. placebo in children withperennial allergic rhinitis and asthma, sensitised to housedust mites. Allergy 2007;62 Suppl 83:234.

Roberta 2009a {published data only}Roberta A, Milani M, Pecora S. A multicenter, randomised,parallel-group trial assessing compliance to 12-monthtreatment with grass tablets in 259 patients with grass pollenrhinoconjuntivitis. Allergy 2009;64 Suppl 90:146.

Roberta 2009b {published data only}Roberta A, Milani M, Pecora S. Safety, tolerability andefficacy of a grass tablet 12-month treatment: a prospectivemulticenter trial in 259 patients with grass pollenrhinoconjuntivitis. Allergy 2009;64 Suppl 90:464.

Rossi 2005 {published data only}

Rossi RE, Monasterolo G. A pilot study of feasibility of ultra-rush (20-25 minutes) sublingual-swallow immunotherapyin 679 patients (699 sessions) with allergic rhinitis and/or asthma. International Journal of Immunopathology andPharmacology 2005;18(2):277–85.

Rukhadze 2008 {published data only}

Rukhadze M, Dolidze N, Abramidze T, Lomidze N, GotuaM, Gamkrelidze A. Allergen-specific immunotherapy inGeorgia. Allergy 2008;63 Suppl 88:529.



Sabbah 1994 {published data only}

Sabbah A, Hassoun S, Le Sellin J, André C, Sicard H. Adouble-blind, placebo-controlled trial by the sublingualroute of immunotherapy with a standardized grass pollenextract. Allergy 1994;49(5):309–13.

Scadding 1986 {published data only}Scadding GK, Brostoff J. Low dose sublingual therapyin patients with allergic rhinitis due to house dust mite.Clinical Allergy 1986;16(5):483–91.

Sieber 2009 {published data only}

Sieber J, Shah-Hosseini K, Moesges R. Grass pollen sitin daily medical practice - effectiveness of sublingualimmunotherapy is comparable with subcutaneoustreatment. Allergy 2009;64 Suppl 90:347.

Stelmach 2009 {published data only}Stelmach I, Kaczmarek-Wozniak J, Majak P, Olszowiec-Chlebna M, Jerzynska J. Efficacy and safety of high-dosessublingual immunotherapy in ultra-rush scheme in childrenallergic to grass pollen. Clinical and Experimental Allergy2009;39(3):401–8.

Stosovic 2008 {published data only}

Stosovic R, Bogic M, Tomic Spiric V. Long-term efficacyand safety of sublingual immunotherapy in seasonal allergicrhinitis. Allergy 2008;63 Suppl 88:392.

Tari 1990 {published data only}Tari MG, Mancino M, Monti G. Efficacy of sublingualimmunotherapy in patients with rhinitis and asthma dueto house dust mite. A double-blind study. Allergologia etImmunopathologia 1990;18(5):277–84.

Tonnel 2004 {published data only}

Tonnel AB, Scherpereel A, Douay B, Mellin B, Leprince D,Goldstein N, Delecluse P, Andre C. Allergic rhinitis dueto house dust mites: evaluation of the efficacy of specificsublingual immunotherapy. Allergy 2004;59(5):491–7.

Troise 2009 {published data only}

Troise C, Voltolini S, Incorvaia C, La Grutta S, Bignardi D,Frati F. Efficacy and safety of sublingual immunotherapywith a high dose birch extract: a placebo-controlled study.Allergy 2009;64 Suppl 90:465.

Tseng 2008 {published data only}Tseng SH, Fu LS, Nong BR, Weng JD, Shyur SD.Changes in serum specific IgG4 and IgG4/ IgE ratio inmite-sensitized Taiwanese children with allergic rhinitisreceiving short-term sublingual-swallow immunotherapy:a multicenter, randomized, placebo-controlled trial. AsianPacific Journal of Allergy and Immunology 2008;26(2-3):105–12.

Ventura 2009 {published data only}Ventura MT, Carretta A, Tummolo RA, Buquicchio R,Arsieni A, Murgia N. Clinical data and inflammationparameters in patients with cypress allergy treatedwith sublingual swallow therapy and subcutaneousimmunotherapy. International Journal of Immunopathologyand Pharmacology 2009;22(2):403–13.

Wessner 2001 {unpublished data only}

Wessner DB, Wessner S, Mohrenschlager M, Rakoski J,Ring J. Efficacy and safety of sublingual immunotherapy inadults with allergic rhinoconjunctivitis: results after 2 yearsof a controlled trial. Allergy 2001;56 Suppl 68:88.

Worm 2006 {published data only (unpublished sought but not used)}Worm M. Efficacy and tolerability of high dose sublingualimmunotherapy in patients with rhinoconjunctivitis.European Annals of Allergy and Clinical Immunology 2006;38(10):355–60.

Worm 2009 {published data only}

Worm M. ’Well Days’ after sublingual immunotherapy witha high-dose 6-grass pollen preparation. Allergy 2009;64(7):1104–5.

Yuksel 1999 {published data only}Yuksel H, Tanac R, Gousseinov A, Demir E. Sublingualimmunotherapy and influence on urinary leukotrienesin seasonal pediatric allergy. Journal of InvestigationalAllergology and Clinical Immunology 1999;9(5):305–13.

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$ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Andre 2003

Methods Study design: Randomised, parallel-group, double-masked and placebo controlled clinicaltrial

Participants Country: FranceSetting: Specialist careNumber randomised: 110 participantsAge: Children and adultsGender: Female 59% (n = 65)Inclusion criteria: Age between 7 and 55 years, an allergy to ragweed pollen as assessedby a clinical history (seasonal allergic rhinitis), positive skin-prick tests and specific IgE(positive RAST class II and above).Exclusion criteria: Patients with symptomatic polysensitisations, asthma not controlled bybeta 2-agonists, current treatment with long-acting antihistamine agents, beta-blockingagents (even topical), inhaled or oral corticosteroids, cromones.

Interventions SLIT: Standardised ragweed extract. Solution and then tablets.Placebo: Solution and then tablets with an appearance similar to that of the active agent.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (grittiness, redness, itching, watery eyes)Ocular medication scores

Notes Allergen: RagweedParticipants numbers for total and individual ocular symptom scores were 26 for activeand 48 for placebo groups (Table 4, p 166), whilst for ocular medications were 44participants for active and 45 for placebo according information provided for authors.Twenty-six participants received the highest dose of SLIT during the study (3 tablets 3times a week).Potential conflicts of interest: First author works with Stallergènes, Antony, France

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk Participants were randomised but how thiswas done was not stated.

Allocation concealment (selection bias) Unclear risk Not stated in paper.

Blinding (performance bias and detectionbias)All outcomes

Low risk Investigators and participants were maskedto treatment assignment for the durationof the study.



Andre 2003 (Continued)

Incomplete outcome data (attrition bias)All outcomes

Low risk Participants lost to follow-up or excludedwere accounted for along with participantsfollowed to designated follow-up periods.

Selective reporting (reporting bias) Low risk The specified outcomes in the methodol-ogy were reported in the results section.

Other bias Low risk No other sources of bias were detected orsuspected.

Ariano 2001

Methods Study design: Randomised, parallel-group, double-masked and placebo controlled clin-ical trial

Participants Country: ItalySetting: Specialist careNumber randomised: 20 participantsAge: AdultsGender: Female 55% (n = 11)Inclusion criteria: Rhinoconjunctivitis and/or mild asthma associated with Cupressaceaepollen, positive skin tests, positive RAST, positive nasal provocation test.Exclusion criteria: Not described.

Interventions SLIT: The active traitment consisted in an aqueous solution of an allergic fraction ofCupressus arizonica partially purified through dialysis in a physiological solution with 15% glycerin. As previously stated, the extract was standardised according to the followingassociated methods: RAST inhibition and Histamine equivalency. The titration wascarried out in RAST UNIT/ml. The participants were instructed to keep the liquid forat least 2 minutes under the tongue before swallowing it (SLIT-SWALLOW technique).Treatment model: there was 5 vials with the following concentrations (vial n.º 1: 100 URAST/ml; vial n.º 2: 300 U RAST/ml; vial n.º 3: 1,000 U RAST/ml; vial n.º 4: 4,000U RAST/ml; vial n.º 5: 10,000 U RAST/ml). The initial phase which lasted 50 daysconsisted in taking 5 drops every day from vial 1 to vial 5. During the maintenancetreatment which lasted 6 months, participants had to take drops of vial 5 every otherday. The total average cumulative dosis was 250,000 U RAST for each patient which is5 times more than the usual dosage in classical subcutaneous immunotherapy.Placebo: No details provided.

Outcomes Total ocular symptom scores

Notes Allergen: Cupressus arizonicaPotential conflicts of interest: Anallergo s.r.l. Firenze, Italy

Risk of bias




Ariano 2001 (Continued)







Low risk All participants completed the study.


Other bias Unclear risk Insufficient information to assess whetheran important risk of bias exists.

Aydogan 2007

Methods Study design: Randomised, parallel-group, double-masked and placebo controlled clin-ical trial

Participants Country: TurkeySetting: Specialist careNumber randomised: 18 participantsAge: ChildrenGender: Male 11 and female 4 (per protocol population)Inclusion criteria: Children with diagnosis of allergic rhinitis sensitised to house dustmites.Exclusion criteria: No details provided.

Interventions SLIT: Standardised 300 IR D. Pteronyssinus + D. farinae 50/50 % extract for a periodof 1 year.Placebo: No details provided.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (redness, itching, watery eyes)

Notes Allergen: MitesAbstract from meetingPotential conflicts of interest: No data available

Risk of bias




Aydogan 2007 (Continued)


Low risk Random number table used.



Unclear risk Investigators and participants were maskedto treatment but how this was done was notstated.


Unclear risk No details were provided.

Selective reporting (reporting bias) Unclear risk Outcomes were described in abstract


Bowen 2004

Methods Study design: Randomised, parallel-group, double-masked and placebo controlled clin-ical trial, multicentre

Participants Country: CanadaSetting: Specialist care (9 allergy centres)Number randomised: 83 participantsAge: Children and adultsGender: ITT population: Male 45 (59%) and female 31 (41%)Inclusion criteria: Patients of either sex, aged 6 to 58 years, with a history of previousseasonal allergic rhinoconjunctivitis during the ragweed pollen season and positive skinprick test reactions to ragweed (3 mm > than the negative control).Exclusion criteria: Symptomatic polysensitisation; asthma not controlled with beta-ago-nist therapy; current therapy with inhaled or oral corticosteroids, beta-blocking agents,long-acting antihistamine agents, or cromones; and previous immunotherapy.

Interventions SLIT: Standardised ragweed allergen extract (Ambrosia eliator). During a 17-day doseprogression phase, the participants received a daily dose of 0.5 to 300 IR. Treatmentwas maintained at the highest tolerated dose (minimum: 100 IR and 116 µg Amb a1; maximum: 20 drops daily, 1 mL, 300 IR/mL, and 314 µg of Amb a 1) during amaintenance phase (pollen season).Placebo: No details provided.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (grittiness, redness, itching, watery eyes)

Notes Allergen: Ambrosia eliatorPotential conflicts of interest: Funded by Stallergènes

Risk of bias



Bowen 2004 (Continued)











Bufe 2004


Participants Country: GermanySetting: Specialist care (33 paediatricians organised in the NETSTAP e.V.)Number randomised: 161 participantsAge: ChildrenGender: No details were providedInclusion criteria: Participants were selected according to a history of summer hay fever.Inclusion criteria were doctors diagnosis of rhinoconjunctivitis, allergic asthma or bothand positive-SPT towards grass pollen allergen extract. Symptoms had to be restrictedto the grass pollen season from May to September.Exclusion criteria: Participants with parallel SPT reactivities to 3 or more other allergengroups (i.e. animal dander, mites, and moulds), with chronic asthma, with previousimmunotherapy or other systemic diseases such as diabetes, leukaemia or immunodefi-ciency.

Interventions SLIT: The build-up phase involved the administration of increasing doses of extract(from 100 allergic units (AU) to 2500 AU/day) for 3 weeks. In the maintenance phaseparticipants received 2500 AU every day. After 3 years participants had ingested a meanof 5250 allergen drops (2.625.000 AU). This was equivalent to a cumulative dosage of9.6 mg major allergen Phl p 5 (timothy grass pollen, data given by HAL-Allergy).Placebo: Placebo containing the solvent used for the treatment extract.



Bufe 2004 (Continued)

Outcomes Combined ocular symptom and medication scores

Notes Allergen: Mix grassPotential conflicts of interest: HAL-Allergy Group

Risk of bias



Low risk Blockwise randomisation was performed.








Bufe 2008


Participants Country: GermanySetting: Specialist care (26 paediatricians organised in the NETSTAP e.V.)Number randomised: 253 participantsAge: ChildrenGender: Male 66% (n = 166)Inclusion criteria: 5 to 16 years of age; at least 1 year clinical history of grass pollen-induced allergic rhinoconjunctivitis having received symptomatic treatment during theprevious grass pollen season; positive skin prick test against P pratense, wheal diameter >3 mm; specific IgE against P pratense, IgE class 2.Exclusion criteria: clinical history of chronic sinusitis or perennial or seasonal allergicrhinitis and/or asthma because of another allergen during-or potentially overlapping-thegrass pollen season; severe asthma; previous treatment by allergen-specific immunother-apy within the previous 5 years or pregnancy.



Bufe 2008 (Continued)

Interventions SLIT: Orodispersible, fast-dissolving, SQ-standardised grass allergen tablet (75,000 SQ-T/2800 bioequivalent allergen units, approximately 15 mg Phl p 5, Phleum pratensemajor allergen 5). The treatment was commenced a minimum of 8 weeks before thestart of the grass pollen season.Placebo: Placebo tablet similar in taste, smell, and appearance.


Notes Allergen: Phleum pratensePotential conflicts of interest: ALK-Abelló

Risk of bias



Low risk Randomisation was performed by stratifi-cation according to trial centre.





Low risk Reported in paper.



Cao 2007

Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial

Participants Country: ChinaSetting: Specialist careNumber randomised: 278 participantsAge: ChildrenGender: Male 174 and female 104Inclusion criteria: Participants aged 4 to 18 years old had to have mild or moderate allergicasthma, allergic rhinitis or both. Skin prick test positive to HDM.Exclusion criteria: Participants were excluded if any evidence of renal, hepatic, cardiacor pulmonary diseases other than asthma was found. Those participants in other drugtrials 4 weeks before the inclusion to this study.



Cao 2007 (Continued)

Interventions SLIT: Treatments were given as daily drops for 25 weeks. Participants were given at thefollowing doses: 1st week: Vial 1. Drops with concentration at 1µg/ml, daily: Mon 1drop, Tue 2 drops, Wed 3, Thu 4, Fri 6, Sat 8 and Sun 10 drops. 2nd week: Vial 2.Drops with concentration at 10µg/ml, daily: Mon 1 drop, Tue 2 drops, Wed 3, Thu 4,Fri 6, Sat 8 and Sun 10 drops. third week: Vial 3 Drops with concentration at 100 µg/ml, daily: Mon 1 drop, Tue 2 drops, Wed 3, Thu 4, Fri 6, Sat 8 and Sun 10 drops. 4thto 25th week: Vial 4: Drops with concentration at 333 µg/ml, daily, 3 drops: 1 drop =40 µL.Placebo: Placebo was a solution with glycerosaline and it matched with the active treat-ment in presentation, quantity, flavour and package.


Notes Allergen: MitesThis trial included 40 pairs of patients with allergic asthma, 32 pairs with allergicrhinoconjunctivitis and 67 with both.Potential conflicts of interest: No data available

Risk of bias













Casanovas 1994


Participants Country: SpainSetting: Specialist careNumber randomised: 15 participantsAge: AdultsGender: Female 73% (n = 11)Inclusion criteria: Clinical history of more than 2 years of evolution; older than 18 years;clinical symptomatology exclusively of rhinitis or rhinoconjunctivitis; skin prick testspositive to Olea pollen and high levels of specific IgE to Olea pollen.Exclusion criteria: Sensitisation to other common aeroallergens and previous im-munotherapy.

Interventions SLIT: Aqueous extract of the pollen of O. europaea standardised on a w/v basis. Treatmentwas preseasonal.Placebo: Glycerinated phenol saline solution.


Notes Allergen: Olea europaeaPotential conflicts of interest: CBF-LETI, S.A. Madrid

Risk of bias








Low risk Participants excluded were accounted foralong with participants followed to desig-nated follow-up periods.


Other bias Unclear risk Insufficient information to assess whetheran important risk of bias exists. Small num-ber of participants across each trial group.



Dahl 2006a

Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial,multicentre

Participants Country: Austria, Denmark, Germany, Italy, The Netherlands, Spain, Sweden, andUnited KingdomSetting: 51 specialist care centres in 8 countriesNumber randomised: 634 participantsAge: AdultsGender: Male 59% (n = 372)Inclusion criteria: 18 to 65 years old; at least 2-year clinical history of significant grasspollen-induced allergic rhinoconjunctivitis; specific IgE against Phleum pratense CAPclass 2; positive skin prick test against Phleum pratense, wheal diameter 3 mm; and FEV1higher than 70% of predicted value.Exclusion criteria: Significant asthma outside the grass pollen season; FEV1 lower than70% of predicted value; allergic rhinitis requiring medication caused by allergens otherthan grass during the treatment period (participants with positive skin tests to otherallergens in the absence of symptoms were permitted); conjunctivitis, rhinitis, or asthmaat the screeningor randomisation visits; history of anaphylaxis; immunosuppressive treatment; receiptof immunotherapy with grass pollen allergen within the previous 10 years or any otherallergen within the previous 5 years; and pregnancy.

Interventions SLIT: Orodispersible grass allergen tablet 75,000 SQ-T (GRAZAX; approximately 15µg major allergen Phleum p 5). The treatment started 16 weeks before the expectedstart of the grass pollen season and continued throughout the grass pollen season 2005.Double-masked treatment continued for another 2 years, followed by 2 years of follow-up. Results from the first treatment season are presented here.Placebo: Tablet similar in taste, smell, and appearance once daily.


Notes Allergen: Phleum pratensePotential conflicts of interest: Funded by ALK-Abelló

Risk of bias



Low risk The allocation sequence was generated bythe sponsoring company and masked forthe investigators.

Allocation concealment (selection bias) Low risk Central allocation.





Dahl 2006a (Continued)


Low risk Participants excluded were accounted foralong with participants followed to desig-nated follow-up periods.



Dahl 2006b


Participants Country: Denmark and SwedenSetting: 15 specialist care centres (11 in Denmark and 4 in Sweden)Number randomised: 114 participantsAge: AdultsGender: Male 68% (n = 77)Inclusion criteria: Age 18 to 65; clinical history of significant grass pollen-induced allergicrhinoconjunctivitis and mild to moderate grass pollen-induced asthma of 2 years ormore; well controlled seasonal asthma in accordance with the GINA Guideline; a positiveskin prick test (wheal diameter %3 mm) and specific immunoglobulin E (IgE; % CAPallergy class 2) to P. pratense.Exclusion criteria: Significant asthma outside the grass pollen season; FEV1 < 70% ofpredicted value; significant allergic rhinitis (requiring medication) caused by allergensother than grass during the planned treatment period; conjunctivitis, rhinitis or asthmaat the screening or randomisation visits; history of anaphylaxis; immunosuppressivetreatment; hypersensitivity to the excipients of the trial medication or rescue medication;having received immunotherapy with grass pollen allergen within the previous 10 yearsor any other allergen within the previous 5 years; pregnancy.

Interventions SLIT: Orodispersible grass allergen tablet 75,000 SQ-T (GRAZAX; approximately 15µg major allergen Phleum p 5). Trial was given 10-14 weeks prior to and during thegrass pollen season 2004.Placebo: Tablet similar in taste, smell, and appearance once daily.


Notes Allergen: Phleum pratensePotential conflicts of interest: Supported by ALK-Abelló

Risk of bias




Dahl 2006b (Continued)


Low risk The allocation sequence was generated bythe sponsoring company and masked forthe investigators.



Low risk Unmasked efficacy and safety assessmentson subject level were available only fora biostatistician at the Contract ResearchOrganization. All personnel associatedwith the study and participants remainedmasked.





de Blay 2007


Participants Country: FranceSetting: 15 specialist care centresNumber randomised: 118 participantsAge: Children and adultsGender: ITT population: Male 69 (66%) and female 35 (34%)Inclusion criteria: Seasonal allergic rhinoconjunctivitis for at least the past 2 years, withor without intermittent asthma (FEV1 80% of the predicted value on enrolment intothe study); (2) sensitisation to grass pollen with positive skin prick test results with a3 grass pollen extract (Dactylis, Phleum, or Lolium); and (3) specific IgE anti-Dactylisantibodies(class 2 or higher) (CAP System; Pharmacia, Uppsala, Sweden).Exclusion criteria: Sensitisation to perennial allergens or to animal allergens if the animalwas present in the patient’s immediate environment, sensitisation to weed and tree pollenwith clinical manifestations, immune diseases, and previous specific immunotherapy forgrass pollen. Use of drugs that might interfere with evaluation of the clinical scores.

Interventions SLIT: SLIT with either a standardised 3 grass pollen extract (33.3% Dactylis glomerata(orchard grass), 33.3% Phleum pratense (timothy grass), and 33.3% Lolium perenne(rye grass), Allerbio, Varennes-en-Argonne, France in 50% glycerin). After a buildup of5 weeks, they reached the maintenance dose, a 300 IR 3 grass pollen extract 3 times aweek. By the end of the study, each patient in the active treatment group had received a



de Blay 2007 (Continued)

mean cumulative dose of 31,800 IR of the 3 grass pollen extract, corresponding to 2.75mg of group 5 grass pollen major allergen.Placebo: Placebo (phenol-free saline solution in 50% glycerin).

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (red, itchy, watery eyes)Ocular medication scores

Notes Allergen: Grass mixPotential conflicts of interest: Supported by Allerbio Laboratory

Risk of bias



Unclear risk Participants were randomised but it is notstated in the paper how it was done.








Didier 2007


Participants Country: Austria, Bulgaria, Czech Republic, Denmark, France, Germany, Hungary, Italy,Slovakia and SpainSetting: 42 specialist care centres in 10 European countries (Austria, 1 cent er; Bulgaria, 6;Czech Republic, 7; Denmark, 1; France, 10; Germany, 7; Hungary, 3; Italy, 2; Slovakia,3; Spain, 2)Number randomised: 628 participantsAge: AdultsGender: ITT population: Male in placebo (60%); SLIT 100 IR (51%); 300 IR (54%);500 IR (62%).Inclusion criteria: Age 18 to 45 years old, all of whom had moderate-to-severe seasonal



Didier 2007 (Continued)

grass pollen-related allergic rhinoconjunctivitis for at least 2 years, confirmed by a positiveskin prick test (wheal size % to 3 mm) and serum specific IgE of at least class 2 (CAPSystem; Phadia, Uppsala, Sweden) to grass pollen assessed at the screening visit. The skinprick test included 5 grass pollens (orchard (Dactylis glomerata), meadow (Poa pratensis), perennial rye (Lolium perenne), sweet vernal (Anthoxanthum odoratum), and timothy(Phleum pratense) grasses), and the RAST of timothy grass was reported in kUnit/L.Participants were investigated for sensitisation to other allergens by testing with the 10most common allergens in each country. Participants sensitised to allergens other thangrass pollen were included as well as those with asthma requiring treatment only withbeta 2-agonists.Exclusion criteria: The main exclusion criteria were allergic rhinoconjunctivitis causedby a co-sensitisation likely to influence symptoms of the patient throughout the studyor symptoms of rhinoconjunctivitis during the treatment phase because of sensitisationto allergens other than grass pollens, previous specific immunotherapy (SIT) for grasspollen, and the usual contraindications for SIT.

Interventions SLIT: Each SLIT tablet contained a mixture of equal proportions of 5 grass pollens:orchard, meadow, perennial rye, sweet vernal, and timothy grasses. Participants weregiven 1 of 3 daily doses (100 IR, 300 IR, or 500 IR) of the SLIT tablets. The meandosage of 300 IR/mL corresponded to approximately 25 mg/mL of the group 5 majorallergens. In November 2004, approximately 5 months before the expected start of thepollen season, participants were screened for eligibility and randomised 1:1:1:1 to 1 ofthe 4 treatment groups (100 IR, 300 IR, 500 IR, or placebo). During the first 5 days oftreatment, doses were increased by 100 IR until the final dose was achieved. The 300 IRdose demonstrated a significant efficacy compared with placebo, therefore this dose waschosen by the authors as a therapeutic dose for clinical practice.Placebo: The placebo tablet matched the active treatment in size, shape, and colour butcontained no pollen allergens or other active ingredients.


Notes Allergen: Grass mixPotential conflicts of interest: Supported by Stallergènes

Risk of bias



Low risk Computer-generated randomisation listutilised.



Low risk Both investigators and participants weremasked to allocation. To maintain themasking, participants took 2 tablets per dayduring the first 5 days of titration and 1tablet per day from day 6 until the end of



Didier 2007 (Continued)

treatment.





Dubakiene 2003


Participants Country: The NetherlandsSetting: Specialist careNumber randomised: 119 participantsAge: Children and adultsGender: Female 54%Inclusion criteria: Participants with allergic complaints, positive SPT for trees (wheal > 4mm) and positive IgE trees.Exclusion criteria: Data not available.

Interventions SLIT: Combination birch / alder / hasel. 5 drops/day = 0.25 mL, cumulative dose is 30mL. Mean treatment duration 4 months.Placebo: Not described


Notes Allergen: Tree pollenPotential conflicts of interest: HAL-Allergy

Risk of bias



Low risk Randomisation in blocks of 4 was per-formed (2 SLIT and 2 placebo).

Allocation concealment (selection bias) Unclear risk Not reported.


Unclear risk Investigators and participants were maskedto treatment but how this was done was notstated in the paper.



Dubakiene 2003 (Continued)


Low risk Participants lost to follow-up or excludedwere analysed.

Selective reporting (reporting bias) Unclear risk It is not reported in the abstract.

Other bias Unclear risk This paper has not been published.

Durham 2006


Participants Country: Belgium, Denmark, Germany, Sweden, Austria, Norway, the United Kingdomand CanadaSetting: 55 specialist care centres in centres in Europe and CanadaNumber randomised: 855 participantsAge: AdultsGender: Male 62% (n = 533)Inclusion criteria: 18 to 65 years of age who gave a clinical history of troublesome symp-toms of allergic rhinoconjunctivitis during the grass pollen season of a duration of at least2 years, a positive skin prick test to P pratense (wheal diameter % 3 mm), raised serumallergen-specific IgE to P pratense, and no significantly abnormal findings on physicalexamination.Exclusion criteria: Clinical history of significant asthma outside the grass pollen season;FEV1 < 70% of the predicted value; significant allergic rhinitis (requiring medication)caused by allergens other than grass during the planned treatment period; significantrecurrent acute sinusitis or chronic sinusitis; conjunctivitis, rhinitis, or asthma at thescreening or randomisation visits; a history of anaphylaxis or angioedema; presence ofserious underlying conditions; immunosuppressive treatment; hypersensitivity to excip-ients of trial medications or rescue medications; or having received immunotherapy withgrass pollen allergen within the previous 10 years or any other allergen within the previ-ous 5 years. Pregnant women and those at risk of pregnancy were also excluded.

Interventions SLIT: Active treatment involved an orodispersible, fast-dissolving grass allergen tablet(ALK-Abelló A/S) containing a standardised grass allergen extract from timothy grass (Ppratense). Participants received 2500, 25,000 or 75,000 SQ-T. Respectively, this corre-sponded to approximately 0, 0.5, 5, or 15 mg P pratense major allergen (Phl p 5).Placebo: Tablet similar in taste, smell, and appearance once daily.


Notes Allergen: Phleum pratensePotential conflicts of interest: Supported by ALK-Abelló

Risk of bias



Durham 2006 (Continued)



Low risk The allocation sequence was generatedby the sponsoring company and maskedfor the investigators (computer-generatedschedule).



Low risk Investigators and participants were maskedto treatment assignment for the durationof the study. Tablet similar in taste, smell,and appearance.





Feliziani 1995


Participants Country: ItalySetting: 2 specialist care centres (Parma and Lanciano)Number randomised: 34 participantsAge: 14 to 48 years old (Inclusion criteria)Gender: Not specifiedInclusion criteria: Sensitisation only to grass pollen proved by means of skin prick testand/or RAST; at least 2 years of oculo-rhinitis with or without asthma, clearly related tothe grass pollen season.Exclusion criteria: Severe asthma, nasal polyps, pregnancy, continuous treatment withsteroids, chronic diseases of the airways, auto-immune diseases, specific immunotherapyin progress or interrupted 5 years before to this study, no compliance.

Interventions SLIT: It was a biologically standardised extract of 5 grasses, graded into 6 strengths:0.04, 0.2, 1, 5, 25, 100 BU/mL. The allergen solution contained 50% V/V of glyceroland 0.4% W/V of phenol as preservative in physiological saline. A schedule of rushpre-seasonal treatment was followed, with drops to be taken sublingually twice a daybetween meals, starting from 1 drop (0.04 BU/mL) up to 5 drops of the same vial andthen repeating the same procedure up to 5 drops of the 100 BU/mL or the maximumlower dose well tolerated. A co-seasonal maintenance treatment then followed with thetop dose reached (on average 5 drops of 100 BU/mL, corresponding to about 20 BU)to be taken 3 times a week until the end of the pollen season.



Feliziani 1995 (Continued)

Placebo: Identical solution prepared in identical vials with the same appearance, colour,taste but without the allergens.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (red and itchy eyes)

Notes Allergen: Grass mixPotential conflicts of interest: Neo-Abelló

Risk of bias



Low risk Treatments were coded according to a keyunknown to the clinician and to the patientand they were assigned randomly to eachpatient.

Allocation concealment (selection bias) Unclear risk This is not reported in the paper.







Hirsch 1997


Participants Country: GermanySetting: Specialist careNumber randomised: 30 participantsAge: ChildrenGender: Male 20 and female 10Inclusion criteria: Clinical history of allergic asthma, allergic rhinitis or both. All partic-ipants were allergic to Dermatophagoides pteronyssinus (D.pt.) documented by posi-tive skin prick test, specific IgE (D.pt.) of > Class 2 (Pharmacia CAP), 3. positive nasalprovocation response to D.pt. (> 40% flow reduction or 60% increase of nasal resistanceto 8000 SBU/ml resp. 4.2 pg/ml Der p 1).



Hirsch 1997 (Continued)

Exclusion criteria: Previous immunotherapy with D.pt., use of oral steroids, or any othersignificant illness.

Interventions SLIT: Active treatment involved a purified whole mite hody extract in 50% aqueousglycerol (Allergopharma J. Ganzer KG, Reinhek, FRG) over 12 months. In a 3-weekbuild-up phase participants took daily increasing doses from 1 to 7 drops of a 1:100dilution of the final preparation in the first week, 1 to 7 drops of a 1:10 dilution in thesecond week, and 1 to 7 drops of the final preparation in the third week. Maintenancewas given as 7 drops on 3 days per week. The Der p I content of the active preparationwas 11.9 µg/ml, so 1 drop (= 0.045 ml) contained 0.535 µg. The cumulative dose Derp I in 12 months was estimated to be approximately 570 µg.Placebo: Vehicle alone.


Notes Allergen: MitesPotential conflicts of interest: Not declared

Risk of bias



Low risk Participants were randomised according toa code provided by the manufacturer.








Horak 1998


Participants Country: AustriaSetting: Specialist care centreNumber randomised: 41 participants



Horak 1998 (Continued)

Age: AdultsGender: Male 15 and female 26Inclusion criteria: Participants suffering from seasonal allergic rhinoconjunctivitis of atleast 2 years of duration, positive skin prick test to Betula alba extract, positive conjunc-tival test (itching and red eyes induced by 1 drop pf a Betula alba extract (30 BU/mL), positive nasal provocation test (100 BU/mL) and increased specific IgE to betula albaby the RAST method were included.Exclusion criteria: Participants who received specific immunotherapy during the last2 years, pregnant and nursing women and participants with contraindications to im-munotherapy were excluded.

Interventions SLIT: Treatment consisted in a biologically standardised extract of Betula alba (Alergia eInmunologia Abelló, S.A.). Schedule started with 1 drop of a 4 STU/mL solution. Thedose was increased in a daily manner (1, 2, 4, 6, 8, 10, 10) in order to reach 10 dropsat the end of each week. This schedule was repeated with the concentrations 20, 100and 500 STU/mL after 4 weeks and using the 500 STU/mL solution, the extract wasadministered every other day (3 times a week for 3 months).Placebo: Saline solution containing 50% glycerine, 0.4% phenol and 0.01% of menthol.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (red, watery and itchy eyes)Conjunctival immediate allergen sensitivity

Notes Allergen: Betula albaEvaluation post-challengePotential conflicts of interest: Not declared

Risk of bias




Allocation concealment (selection bias) Unclear risk This is not reported in the paper.


Low risk Investigators and participants were maskedto treatment assignment for the durationof the study. The bottles for the treatmentand their contents were identical in tasteand layout in order to guarantee the dou-ble-mask of the trial. Vials content was un-known to the research team and the partic-ipants.





Horak 1998 (Continued)



Khinchi 2004


Participants Country: DenmarkSetting: Specialist careNumber randomised: 71 participantsAge: Adults (20 to 58 years old)Gender: SLIT: 11 male and 7 female; placebo 12 male and 7 femaleInclusion criteria: Participants with at least 2 years of seasonal birch pollen rhinoconjunc-tivitis uncontrolled by conventional pharmacotherapy were enrolled. Birch pollen allergywas verified by a positive skin prick test and a positive conjunctival provocation test usinga standardised extract, and the presence of specific IgE (RAST) class 2) using the CAPSystem. Participants with mild seasonal birch pollen induced asthma were accepted forinclusion.Exclusion criteria: Perennial allergy, chronic, nonallergic rhinitis or sinusitis, previousimmunotherapy with birch pollen within the last 5 years or ongoing immunotherapywith other allergens, treatment with beta-blockers or participants on continuous corti-costeroids, pregnancy or planned pregnancy, participation in another clinical trial andthe standard contraindications for immunotherapy.

Interventions SLIT: Active treatment involved a birch pollen extract standardised in terms of the majorallergen Bet v 1 administered as glycerosaline solution (SLIT, Staloral; Stallergenes SA,Antony, France). The sublingual treatment was self-administered at home. Drops wereheld under the tongue for 2 minutes before swallowing. A 30-day sublingual inductionphase was followed by a maintenance phase of 21 to 23 months. The initial dose was0.0164µg and the top dose 49.2µg Bet v 1 administered every second day. The treatmentschedule was adjusted according to the individual patient’s tolerance.Placebo:The placebo preparations included caramelised sugar for sublingual to ensure anidentical visual appearance and taste for SLIT preparations.

Outcomes Total ocular symptom scoresOcular medication scores (eye drops)

Notes Allergen: Birch pollenBased on the baseline registration 71 participants were allocated into 3 groups: SLIT-group: receiving sublingual immunotherapy (drops) and placebo injections; SCIT-group: receiving subcutaneous immunotherapy (injections) and placebo sublingualdrops; Placebo-group: receiving placebo sublingual drops and placebo subcutaneous in-jections. All study personal and participants were masked to treatment assignment forthe 2-year duration of treatment in the study.Potential conflicts of interest: Supported by Stallergènes



Khinchi 2004 (Continued)

Risk of bias



Low risk Randomisation was performed by minimi-sation based on disease severity during thebaseline season, gender and age.

Allocation concealment (selection bias) Unclear risk No details were provided.


Low risk All study personal and participants weremasked to treatment assignment for the 2-year duration of treatment in the study.





La Rosa 1999


Participants Country: ItalySetting: Specialist care centreNumber randomised: 41 participantsAge: Children (6 to 14 years old)Gender: Male 25 and female 16Inclusion criteria: Participants with a positive history of rhinoconjunctivitis, with orwithout mild intermittent asthma, caused by Parietaria pollen sensitisation documentedby positive skin tests (wheal diameter > 4 mm) and positive radioallergosorbent testresults (class II and above).Exclusion criteria: Participants with uncontrolled asthma, symptomatic polysensitisationor who were treated with beta-blockers or long-acting corticosteroids were excluded.Participants with cats at home were also excluded.

Interventions SLIT: Active treatment consisted of a standardised P judaica extract (Stallergènes, Antony,France) in drops to be taken sublingually and held under the tongue for 2 minutes beforebeing swallowed. The extract was standardised in index of reactivity (IR) units. Thelevel of the Par J 1 major allergen in the 100 IR extract was 70 mg/mL. The build-uptreatment phase started with 2 drops of the first concentration (1 IR/mL), increasing by2 drops per day up to 10 drops per day, followed by the next concentration (10 IR/mL)



La Rosa 1999 (Continued)

increasing from 2 to 10 drops per day and then continued with a similar progression from2 to 20 drops of the next concentration (100 IR/mL) and 2 to 20 drops of the highestconcentration (300 IR/mL). After administration of 20 drops of 300 IR per millilitredaily for 1 month, the maintenance dose was 20 drops of 300 IR per millilitre 3 timesa week until the end of the study. The cumulative dose of allergen extract received byeach patient was 75,000 IR per year. The cumulative dose of Par J 1 major allergen was52.5 mg over 2 years.Placebo: Placebo consisted of a glycerinated phenolated saline solution with an appearanceand taste similar to those of the active treatment.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (red, watery and itchy eyes)

Notes Allergen: Parietaria judaicaPotential conflicts of interest: Supported by Stallergènes

Risk of bias











Moreno-Ancillo 2007


Participants Country: Spain.Setting: 3 specialist care centres (Cordoba, Madrid and Plasencia)Number randomised: 105 participantsAge: Children and adultsGender: Male 55% (n = 58)



Moreno-Ancillo 2007 (Continued)

Inclusion criteria: Participants aged 14 to 55 years with at least 1 year of clinical historyof moderate-severe seasonal allergic rhinitis to grasses and Olea europaea pollen, with orwithout asthma symptoms, were recruited. Positive skin prick tests (mean diameter ofwheal, % 3mm) to grass mix extracts and O europaea were required.Exclusion criteria: Perennial rhinitis or asthma, clinically relevant sensitisation to Der-matophagoides pteronyssinus, Alternaria alternata, cat and/or dog dander, treatmentwith grass or O europaea allergenic vaccines within the 2 years previous to study initia-tion, absolute or relative contraindications to immunotherapy, or any other conditionthat, under the investigators criteria, could compromise the participants safety.

Interventions SLIT: Drops. The extract was biologically standardised by major allergens (grass Group5 and Ole e 1) and quantified inmicrograms. Daily dose contained 2 µg of grass Group 5 and 3 µg of O europaea Ole e1. Immunotherapy was administered for a mean duration of 248 days, including a pre-seasonal treatment period of 207 days.Placebo: Placebo was similar in taste and appearance.

Outcomes Total ocular symptom scoresCombined ocular symptom and medication scores

Notes Allergen: Olea europaeaSignificant intra-group symptom reductions in participants receiving SLIT.Potential conflicts of interest: ALK-Abelló

Risk of bias



Low risk Randomisation in blocks. Asthma diagno-sis was a criterion for stratification.

Allocation concealment (selection bias) Unclear risk It is not reported in the paper.









Mortemousque 2003


Participants Country: FranceSetting: Specialist careNumber randomised: 60 participantsAge: Children and adultsGender: Male 20 and female 10Inclusion criteria: History of perennial conjunctivitis and symptoms after exposition todomestic house dust mites sources. Participants also experienced symptoms not suffi-ciently controlled by topical medications and/or oral antihistamines. IgE-mediated con-junctivitis was demonstrated in all participants selected by positive skin prick tests to D.pteronyssinus (D.pt.) and D. farinae (D.f.) standardised extract, specific IgE (D.pt. andD.f ) positivity (RAST % class 2) and CPT positivity to D.pt.Exclusion criteria: Participants sensitised to cat or dog allergens and living with pets athome were excluded. No patient had previously received immunotherapy with D.pt.,was using oral steroids or had any other significant illness.

Interventions SLIT: Drops. The extract was a D.pt./D.f. preparation in 50% aqueous glycerol. Theduration of treatment was 24 months. Treatment was initiated between January 1997 andMarch 1997 and the study was completed in March 1999. During a 4-week incrementaldose period, participants took daily increasing doses from 1 to 10 drops of the 1 IR/mLvial from day 1 to day 4, then 1 to 10 drops of the 10 IR/mL vial from day 5 to day 8,then 1 to 20 drops of the 100-IR/mL from day 9 to day 15, and finally 5 to 20 drops ofthe 300 IR/mL vial during the next 2 weeks. The highest dose (20 drops from the 300IR/mL vial) was administered daily for 4 weeks and then 3 days per week throughoutthe maintenance phase. An average cumulative dose of 90 000 IR (equivalent to 2.2 mgof Der p 1 and 1.7 mg of Der f 1) of allergens had been administered to each patientundergoing active treatment by the end of the trial.Placebo: The placebo preparation was identical to active treatment in terms of composi-tion, appearance, presentation, taste and colour.

Outcomes Total ocular symptom scoresConjunctival immediate allergen sensitivity


Risk of bias




Allocation concealment (selection bias) Unclear risk No details were given.





Mortemousque 2003 (Continued)





Ott 2008

Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial,multicentre.

Participants Country: GermanySetting: Specialist careNumber randomised: 213 participantsAge: Children (11) and adultsGender: Male 71 and female 74 (ITT population)Inclusion criteria: Participants with grass pollen allergic rhinoconjunctivitis. The diag-nosis was based on clinical history (% 2 years of grass pollen allergy), confirmed by apositive skin prick test (wheal diameter % 3 mm) and the presence of grass pollen-specificserum immunoglobulin (Ig) E reaching a level of at least 0.70 kU/l corresponding toclass 2 in the utilised detection system (CAP System; Phadia, Uppsala, Sweden). Theskin prick test included 5 grass pollens (cocksfoot or orchard grass, Dactylis glomerata;meadow grass, Poa pratensis; perennial rye grass, Lolium perenne; sweet vernal grass, An-thoxanthum odoratum; and timothy grass, Phleum pratense). Participants had to sufferfrom persistent allergic rhinitis (> 4 weeks/year) with a severity requiring treatment bydrugs recommended for participants with mild persistent rhinitis. All participants hadrequired symptomatic treatment during the course of the preceding pollen season andhad planned treatment for the first study season with either oral cetirizine, ocular or nasalazelastine, oral or ocular prednisolone, nasal beclomethasone or inhaled salbutamol.Exclusion criteria: Perennial allergic rhinitis and/or perennial allergic asthma, a total serumIgE level >2000 kU/l, chronic nonallergic rhinitis or sinusitis, atopic dermatitis, severeasthma (mild asthma grade 1 to 2 was accepted), any immunotherapy in the previous5 years and the usual contraindications to immunotherapy. House dust mite sensitivitywas not an exclusion criterion.

Interventions SLIT: A mixture of pollen extracts of 5 grasses (cocksfoot or orchard, meadow, perennialrye, sweet vernal and timothy grasses; Staloral, Stallergenes SA, France) was used at aconcentration of 300 IR/ml (equivalent to 21 µg/ml of Phl p 5; Phleum pratense majorallergen) and administered as sublingual drops. Rush titration was performed under closesupervision. On day 1, participants took 4 increasing doses of SLIT, corresponding to30, 90, 150 and 300 IR, at 20 minute intervals (0, 20, 40 and 60 minutes), followed bya daily intake of 300 IR for the duration of the pollen season. During 3 pollen seasons,participants received study medication or placebo, as randomised.Placebo: 142 participants were randomly allocated to receive placebo, but its character-



Ott 2008 (Continued)

istics were not stated.


Notes Allergen: Grass pollenPotential conflicts of interest: Sponsored by Stallergènes GmbH, Germany

Risk of bias




Allocation concealment (selection bias) Unclear risk No details were stated.


Low risk Investigators and participants were maskedto treatment.





Palma-Carlos 2006


Participants Country: PortugalSetting: Specialist careNumber randomised: 33 participantsAge: AdultsGender: Male 20 and female 13Inclusion criteria: Participants had to have a clinical history of seasonal (intermittent)rhinoconjunctivitis with or without mild intermittent or mild persistent asthma since atleast 2 years. All participants were sensitised to grass pollens, as confirmed by skin pricktest and RAST.Exclusion criteria: Participants suffering from severe systemic and/or autoimmune dis-eases or acquired/congenital immune deficiencies, past or current malignancy, neuro-logical or psychiatric disorder requiring major psychodrugs, receiving chronic systemiccorticosteroid or beta-blocking treatments were not enrolled, nor were pregnant women.



Palma-Carlos 2006 (Continued)

Interventions SLIT: The IT was performed with a mixture of chemically modified allergenic extracts(carbamylated monomeric allergoid) from grass pollens (Holcus lanatus 33%, Phleumpratense 33%, Poa pratensis 33%) incorporated in oromucosal tablets (Lais, LofarmaS.p.A., Milan, Italy). The tablets had to be dissolved in the mouth in 1 to 2 minutesbefore swallowing. Enrolment of the participants was preseasonal followed by a seasonalvisit in May and an end-of-the year visit in October. Participants were followed during 2consecutive years. The initial therapy consisted in a traditional scheme lasting 14 weeks.The maintenance therapy was performed at the posological scheme of 2 tablets of 1000UA per week, given pre-seasonally till May.Placebo: No details were provided


Notes Allergen: Grass mixPreseasonal schedule; tabletsPotential conflicts of interest: Lofarma S.p.A

Risk of bias




Allocation concealment (selection bias) Unclear risk No details were stated in the paper.






Other bias Unclear risk 39.4% of participants withdrew during fol-low-up.

Panzner 2008


Participants Country: Czech RepublicSetting: 9 specialist care centresNumber randomised: 74 participants (sublingual 20, placebo sublingual 15)



Panzner 2008 (Continued)

Age: Children and adultsGender: Sublingual groups: Male 20 and female 15Inclusion criteria: All participants had seasonal rhinitis and/or conjunctivitis (withoutasthma) caused by grass pollen, had experienced symptoms in at least the previous 2 yearsand none of the participants had previous treatment with SIT within the last 5 years.The diagnosis of allergy to grass pollen was made by clinical history, positive skin teststo standardised pollen extract e Grass mixture I and Dactylis glomerata and the presenceof specific IgE to the mixture of grass pollens.Exclusion criteria: Sensitisation to major inhalant allergens coinciding with the grasspollen season e ash (Fraxinus excelsior), lime (Tilia cordata), elderberry (Sambucus ni-gra), dandelion (Taraxacum officinale), plantain (Plantago lanceolata) and nettle (Urticadioica), systemic immunologic or metabolic disease, malignancies, major anatomic al-terations of the upper airways, severe atopic dermatitis, chronic corticosteroid or beta-blocker treatment, pregnancy, chronic or recurrent inflammation of oral mucosa andother contraindications of SIT.

Interventions SLIT: Active treatment was a mixture of 6 species of grass pollens (Grass mixture I): oatgrass (Arrhenatherum elatius), orchard grass (Dactylis glomerata), fescue (Festuca sp.), rye grass (Lolium sp.), timothy grass (Phleum pratense) and rye (Secale cereale). Themaximal dose (10 drops of 10 000 JSK/ml) contains approximately 1.265 mg of the grasspollen major allergen Lol p I. The treatment was started in autumn and was followedby a maintenance therapy with 10 drops of 10 000 JSK/ml 3 times a week for 1 year.The participants using sublingual therapy were instructed to keep the drops under thetongue for 1 to 2 minutes before swallowing them. According to the schedule, by theend of the trial (September 2004), an average total cumulative dose was more than 580000 JSK.Placebo: Placebo preparations were identical to the active therapy in composition, ap-pearance, presentation, taste, and colour, but obviously contained no allergen.

Outcomes Allergen: Grass mixTotal ocular symptom scoresIndividual ocular symptom scores (swelling, redness, itching, watery eyes)

Notes Participants were randomly allocated to 1 of the following 4 groups: Sublingual active,Sublingual placebo, Supralingual active, Supralingual placebo.Potential conflicts of interest: One of the authors is linked to Sevapharma a.s

Risk of bias



Low risk Central randomisation. The randomisa-tion key was generated by the GraphPadSoftware.




Panzner 2008 (Continued)







Passalacqua 1998


Participants Country: ItalySetting: Specialist care centreNumber randomised: 20 participantsAge: Children and adults (age 15 to 46 years old)Gender: Male 7 and female 13Inclusion criteria: The main inclusion criteria were perennial rhinoconjunctivitis anddisease duration of at least 2 years, with or without mild asthma. Sensitisations to allergensother than mites were excluded by skin tests and radioallergosorbent tests (mites, grasses,parietaria plant, cat and dog dander, olive, birch, Alternaria, and Aspergillus).Exclusion criteria: Those participants with systemic immunological disease, majoranatomical alterations of the upper airways, severe atopic dermatitis, were receivingchronic corticosteroid treatment, had previously received immunotherapy, pregnant orlactating women were excluded.

Interventions SLIT: Treatment started in April, 1994, and continued until March, 1996. Immunother-apy consisted of tablets of monomeric allergoid Dermatophagoides pteronyssinus and Dfarinae (LAIS, Laboratorio Farmaceutico Lofarma, Milan, Italy). The tablets were placedunder the tongue, dissolved in the mouth for 1 to 2 minutes, and swallowed. The build-up phase involved the administration of increasing doses of the allergen (25 AU, 50 AU,100 AU, 200 AU, 300 AU, 600 AU, and 1000 AU). Each dose was taken for 3 alternatedays. In the maintenance phase, participants received 2000 AU twice weekly.Placebo: The placebo tablets were identical to immunotherapy in flavour and appearance.



Risk of bias



Passalacqua 1998 (Continued)



Low risk Random codes were used.

Allocation concealment (selection bias) Unclear risk It was not stated in the paper.







Passalacqua 1999


Participants Country: ItalySetting: Specialist care centreNumber randomised: 30 participantsAge: AdultsGender: Male 19 and female 11Inclusion criteria: All participants had seasonal rhinoconjunctivitis (13 with mild inter-mittent asthma) caused by Parietaria pollen and had experienced symptoms in at leastthe 2 previous years. Other sensitisations were excluded by skin testing and RAST (panelincluding mites, pet dander, grass, olive, birch, Alternaria species, and Aspergillus species).Exclusion criteria: Exclusion criteria were systemic immunologic or metabolic disease,malignancies, major anatomic alterations of the upper airways, severe atopic dermatitis,chronic corticosteroid??-blocker treatment, and previous courses of immunotherapy. Nopregnant or lactating women were admitted.

Interventions SLIT: The SLIT (ALK-Abelló) was administered pre-seasonally (from October 15 toMarch 15, 1996), according to a rush schedule. The diary card was recorded again duringthe 1996 pollen season. The extract in glycerinated-phenolated aqueous solution wasprepared in 5 different vials at increasing concentrations (0.016, 0.08, 0.4, 2, and 10BU/mL). During the build-up, the drops had to be taken twice daily, starting with 1drop from the first vial and increasing up to 5 drops and then repeating the procedurewith each vial until the maximum dose was reached (5 drops from the 10-BU/mL vial). This maintenance dose (corresponding to 0.12 µg of Par j 1) was then administered




daily until the beginning of the pollen season. The cumulative dose was 256 BU (about16 µg of Par j 1).Placebo: The placebo was undistinguishable from the active treatment.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (red and itchy eyes)

Notes Allergen: Parietaria judaicaPotential conflicts of interest: Two authors are linked to ALK-Abelló Group, Milan, Italy

Risk of bias




Allocation concealment (selection bias) Unclear risk It was not stated in the paper.







Passalacqua 2006


Participants Country: ItalySetting: Specialist care centresNumber randomised: 68 participantsAge: AdultsGender: Male 28 and female 40Inclusion criteria: Participants had to suffer from mild persistent rhinitis according toARIA guidelines with or without mild intermittent asthma according to Global Initiativeon Asthma (GINA) guidelines since at least 2 years. They had to have a skin positivityto house dust mite (wheal diameter > 5 mm) and a CAP - radioallergosorbent class II orgreater.




Exclusion criteria: (i) systemic immunological disorders; (ii) malignancies; (iii) diabetes;(iv) chronic heart failure or chronic obstructive pulmonary disease; (v) pregnancy orlactation; (vi) skin test positivity to cat/dog dander or Parietaria (this latter allergen isalmost perennial in the Mediterranean area); (vii) any specific IT course in the last 5years and (viii) major psychiatric disorders.

Interventions SLIT: Sublingual immunotherapy was a monomeric carbamylated allergoid (Lais - Lo-farma S.p.A, Milan, Italy) biologically standardised in allergenic units (AU), and pre-pared as soluble tablets. The tablets had to be taken in the morning on an empty stom-ach, and kept under the tongue for 1 to 2 minutes until dissolution before swallowing.During the build-up phase of about 1 month, tablets with increasing dosages (25, 100,300 and 1000 AU) were used in order to gradually achieve the maximum dose of 1000AU. Subsequently, that maintenance dose of 1000 AU was administered 2 times a weekfor 2 years continuously.Placebo: Placebo tablets contained the same excipients without the allergoid and wereundistinguishable in aspect, flavour and dissolution time from the active treatment.

Outcomes Individual ocular symptom scores (Itchy eyes)

Notes Allergen: MitesPotential conflicts of interest: Lofarma S.p.A

Risk of bias



Low risk A computer-generated list was used.

Allocation concealment (selection bias) Unclear risk It is not stated in the paper.









Pfaar 2008


Participants Country: Germany, Poland and MacedoniaSetting: 11 specialist care centresNumber randomised: 185 participantsAge: Adults (17 to 59 years old)Gender: Male 116 and female 69Inclusion criteria: 1) diagnosed as having IgE-mediated grass pollen allergic rhinitis orrhinoconjunctivitis, with or without bronchial asthma (Global Strategy for Asthma Man-agement and Prevention program I or II criteria); 2) the existence of a positive skin pricktest wheal result with a 6 grass pollen extract equal to or greater than the histaminecontrol (0.1%) or greater than 5 mm in diameter; 3) the existence of a positive radioal-lergosorbent test result or of CAP enzyme allergosorbent test class 2 or greater (% 0.7kU/L); 4) a positive conjunctival provocation test result with grass pollen allergens; and(5) reported rhinitis or conjunctivitis symptoms during the baseline season (participantsmust have had a symptom score of % 4 from a possible maximum of 30 on each day inthe week after the peak pollen count).Exclusion criteria: Exclusion criteria were as follows: previous grass pollen immunother-apy, symptoms related to or positive skin prick test result at least as large as the histaminecontrol or greater than 5 mm in diameter to other allergens relevant in the grass pollenseason (e.g. tree pollen, weeds, moulds, cat, or mites), pregnancy, intake of beta-blockersor angiotensin-converting enzyme inhibitors, long-term treatment with systemic corti-costeroids or long-acting antihistamines, intake of long-acting beta 2-agonists or nasalcorticosteroids during the grass pollen season, and cardiovascular, immunological, orother medically relevant diseases.

Interventions SLIT: It contained pollen allergens of 6 grass species (Holcus lanatus, Dactylis glomerata,Lolium perenne, Phleum pratense, Poa pratensis, and Festuca elatior). The allergen extractwas standardised to the content of the group 5 grass allergen. The group 5 allergen contentof the maintenance dose was 40 µg, as measured in 1 enzyme-linked immunosorbentassay (ELISA) system, and 20 µg, as measured with a recombinant reference preparationand assay, as tested in the CREATE project. The latter is most likely to conform to afuture biological reference system. The study solution was applied to and kept underthe tongue for 3 minutes and swallowed thereafter. Dose escalation was performed atthe investigators’ site on the first day of treatment, with a doubling of the dose every60 minutes: initial dose, 25% (1 drop), then 50% (2 drops), and then 100% (4 drops)of the maintenance dose, corresponding to 10, 20, and 40 µg of the group 5 grassallergen. This was followed by daily self-administration of the maintenance dose by theparticipant. If the full maintenance dose was not tolerated, the dose was temporarilyreduced to 75%, 50%, 25%, or 0% and readjusted individually, if possible, to the fulldose after consultation with the study physician. The baseline evaluation was during thegrass pollen season in 2003 and a treatment phase from January 2004 until the end ofthe grass pollen season in 2005.Placebo: Matching placebo was identical in colour, taste, and smell and did not containactive ingredients.

Outcomes AUC of the ocular symptom-medication-score (SMS)



Pfaar 2008 (Continued)

Notes Allergen: Grass mixPotential conflicts of interest: Supported by Allergopharma

Risk of bias



Low risk A block randomisation was performed, andthere was a stratification procedure with re-spect to asthma.








Pradalier 1999


Participants Country: FranceSetting: 20 specialist care centres (Paris area 5, Nantes 9, Orléans 2, Valence 3, Le Creusot1)Number randomised: 126 participants (ITT, n = 123)Age: Children (17) (7 to 15 years old) and adults (109)Gender: Male 65 and female 58Inclusion criteria: Participants had to have grass pollen related seasonal rhinitis, allergicconjunctivitis or mild asthma. The diagnosis of grass-pollen allergy was based on asuggestive clinical history, a positive prick test to 1 of the pollens in the 5 grass pollenextract (Stallergènes SA, Antony, France), and a positive assay for specific IgE to orchardgrassor timothy grass with the CAP System.Exclusion criteria: Clinically relevant sensitisation to house dust mites (Der-matophagoides pteronyssinus/D. farinae), cockroach, Alternaria, and pollens releasedduring the same season as grass pollens. Allergy to cat and/or dog dander was an exclusioncriterion only if the pet lived in the participant’s home. Asthmatic patients whose treat-ment included medications other than beta 2-agonists taken as needed were excluded, as



Pradalier 1999 (Continued)

were participants who had received immunotherapy with 1 of the pollens in the 5 grasspollen extract within the last 2 years.

Interventions SLIT: The standardised 5 grass pollen extract (Stallergènes SA, Antony, France) usedthroughout the study was a mixture of orchard grass, meadow grass, ryegrass, sweet vernalgrass, and timothy grass pollens. Its biologic activity was evaluated with RAST inhibitionin comparison with an internal standard in in vitro and in vivo tests, and was expressedas the index of reactivity (IR) defined as follows: a prick test with an extract containing100 IR/ml produces a wheal with a mean geometric diameter of 7 mm in 30 participantssensitised to the allergen under consideration. The amount of the timothy major allergenPhl p 5 in 100-IR extract was 8.5 µg/mL. The study treatment was given from March1996 to July 1996. The treatment included a 15-day progression of doses phase (Table1), during which the extract was given each morning as sublingual drops prepared with aglycerosaline diluent (Stallergènes SA, Antony, France) containing 1, then 10, and finally100 IR/ml. The participants were instructed to keep the drops under the tongue for 2minutes before swallowing them. When the 100-IR dose was reached (20 drops fromthe 100-IR/ml bottle), the drops were replaced by once-daily administration of a singlesublingual tablet containing 100 IR, until 7 July 1996. The cumulative allergen dosein the active treatment group was about 11 000 IR corresponding to 0.935 mg of thetimothy pollen major allergen Phl p 5.Placebo: The placebo drops and tablets were similar to the active agent in terms ofappearance, taste, and packaging. In both groups, the extract as sublingual drops was alimpid, colourless solution, with a sweet taste and smell. Active and placebo tablets werewhite, with a slightly sweet taste but no smell.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (grittiness, redness, itching, watery eyes)Ocular medications scores (eye drops)

Notes Allergen: Grass mixDrops and tabletsPotential conflicts of interest: Two authors are linked to Stallergènes

Risk of bias




Allocation concealment (selection bias) Unclear risk No details were provided in the paper.







Pradalier 1999 (Continued)



Purello-D’ Ambrosio 1999


Participants Country: ItalySetting: Specialist care centreNumber randomised: 30 participantsAge: AdultsGender: Male 14 and female 16Inclusion criteria: Participants were enrolled if they had had symptoms of allergicrhinoconjunctivitis with or without moderate asthma (FEV1 values of 70±90% of pre-dicted values) for at least 2 years during the Parietaria pollen season and a skin pricktest positive for the P. judaica. Specific IgE to P. judaica levels in sera were determinedby the RAST EIA technique (Pharmacia Diagnostics AB, Uppsala, Sweden), and onlyparticipants showing at least a class 3 result were selected for the trial.Exclusion criteria: Exclusion criteria were severe asthma (FEV1 values below 70% of pre-dicted values), previous specific immunotherapy, sensitisation to other inhalant allergens,pregnancy, or other general contraindications for immunotherapy as established in theEAACI position paper.

Interventions SLIT: The therapy consisted of 5 3-ml vials with a concentration of 0.016 BU/ml (vial0), 0.08 (vial 1), 0.04 (vial 2), 2 (vial 3), and 10 (vial 4) in physiologic saline with50% v/v of glycerol and 0.4% w/v of phenol. The major allergen Par j 1 content inthe vial with the maximum concentration was 0.6 µg/ml. The treatment schedule wasstarted in January, before the beginning of the P. judaica pollination period, after a 2-week rush-inducing schedule. The drops were to be taken from the different vials, andhad to be taken twice daily, starting with 1 drop from vial 0 and increasing by 1 dropat each administration up to a dose of 5 drops of the same vial and then repeating theprocedure with the subsequent vials. The maximum dose of 5 drops from vial 4 was thenadministered 3 times a week. This maintenance dosage was continued until the end ofSeptember. According to the schedule, by the end of the trial, an average cumulative doseof 199.5 BU of allergen had been administered to each patient in the active sublingualtherapy group, equal to 12.77 µg of Par j 1.Placebo: Placebo preparations were identical to the active therapy in composition, ap-pearance, presentation, taste, and colour.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (itching and red eyes)

Notes Allergen: Parietaria judaicaPotential conflicts of interest: Two authors are linked to ALK-Abelló



Purello-D’ Ambrosio 1999 (Continued)

Risk of bias











Rolinck-Werninghaus 2004


Participants Country: GermanySetting: 4 specialist care centres (Berlin, Freiburg, Dresden, Munich)Number randomised: 97 participantsAge: ChildrenGender: Male 65 and female 32Inclusion criteria: Children aged 3 to 14 years with seasonal allergic rhinitis with specificIgE to grass pollen (CAP-class % 2), a wheal size of % 3 mm or a skin index of % 0.6 inSPT, and a positive CPT at a specific allergen concentration # 100 000 SQ-U/ml.Exclusion criteria: Exclusion criteria were perennial asthma with a need for permanenttopical or systemic corticosteroid treatment, atopic dermatitis with a need for permanenttreatment with corticosteroids, systemic treatment with corticosteroids or immune sup-pressive drugs within the 4 weeks before the start of the study, perennial allergic rhini-tis, treatment with SIT within the 3 years before the start of the study and the knowncontraindications of SIT according to the EAACI position paper.

Interventions SLIT: Participants in the active group were treated with standardised allergens from a5 grass mixture composed of Dactylis glomerata, Festuca pratensis, Lolium perenne,Phleum pratense and Poa pratensis in equal parts suspended in physiologic saline solutionwith 50% glycerol and 0.3% phenol (Pangramin SLIT; ALK-SCHERAX, Hamburg,



Rolinck-Werninghaus 2004 (Continued)

Germany). The potency was expressed in specific treatment units (STU); 1000 STUwere equivalent to 25 biological units (BU) and contained 2.5 µg of major grass pollenallergens. The monthly dose during maintenance treatment was 6 µg (0.5 µg/dose, 3times/week). The median for the total duration of treatment was 32 months (January1999 to November 2001) with a median cumulated dose of 188 µg allergens. Childrenwere instructed to applicate the relating amount of the SLIT preparation under thetongue and to wait for 3 minutes before swallowing. Initial treatment of SLIT was appliedfrom 5 vials (0 to 4) with the concentrations 1.6, 8, 40, 200 and 1000 STU/ml beginningwith 1 drop from vial 0 taken on days 1 and 2 and continued by 2 drops on days 2 and3 until reaching 5 drops on days 9 and 10. The dose was then increased by 1 drop/dayfrom 1 to 5 drops from vials 1 to 4. Total duration of the initial treatment was 4 weeks.The dose of 5 drops from vial 4 was applied as a maintenance dose 3 times a week untilthe end of the 32 months treatment period.Placebo: Placebo vials contained the Pangramin solution without allergen.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (grittiness, redness, itching, watery eyes)Conjunctival immediate allergen sensitivity

Notes Allergen: Grass mixThe adjusted symptom scores (to 1000 pollen/m3) in 6 weeks with peak pollen countsin the third grass pollen season were includedPotential conflicts of interest: Alk-Scherax

Risk of bias



Low risk Randomisation was conducted for age andhistory of asthma in consecutive order atinclusion.










Röder 2007


Participants Country: The NetherlandsSetting: Primary care (64 general practices)Number randomised: 204 participantsAge: Children (6 to 17 years old)Gender: ITT population: Male 95 and female 73Inclusion criteria: Inclusion criteria were IgE antibodies to grass pollen % 0.7 kU/L anda history of rhinoconjunctivitis, assessed by a retrospective symptom score: participantsscored 5 symptoms (sneezing, itching nose, watery running nose, nasal blockage, anditching eyes) during the previous grass pollen season (May to August) on a 0 to 3 scale(0 = none, 1 = mild, 2 = moderate, 3 = severe; maximum total score = 15). Participantswith a retrospective total symptom score % 5 were included.Exclusion criteria: Exclusion criteria included the use of daily pulmonary inhaled gluco-corticoids during % 3 months in the preceding year, immunotherapy in the preceding3 years, sensitisation to pets in the family home (specific IgE % 0.7 kU/L), nasal abnor-malities requiring surgery, and contraindications for immunotherapy.

Interventions SLIT: Participants underwent verum treatment with a mixture of aqueous extracts of 5grass pollen species (Lolium perenne, Phleum pratense, Dactylis glomeratein, Anthoxantumodoratum, and Holcus lanatus; Oralgen Grass Pollen; Artu Biologicals, Lelystad, TheNetherlands) in a glycerinated isotonic phosphate-buffered solution. Treatment startingwith a single drop containing 475 biological units (BU) of allergen was increased with 1drop daily until day 20. The maintenance dose was 20 drops (9,500 BU; 21 µg equivalentLol p 5) twice weekly for 2 years, resulting in a mean cumulative dose of 1,976,000 BU(4.5 mg equivalent Lol p 5). The drops were administered sublingually and kept therefor at least 1 minute before being swallowed.Placebo: Placebo treatment consisted of the solvent.

Outcomes Individual ocular symptom scores (itchy eyes)

Notes Allergen: Grass mixPotential conflicts of interest: Supported by Artu Biologicals

Risk of bias



Low risk A computer-generated randomisation liststratifying for symptom score and partici-pating general practice was utilised.

Allocation concealment (selection bias) Low risk A pharmacist allocated medication in ac-cordance with a computer-generated ran-domisation list stratifying for symptomscore and participating general practice.Participants, parents, investigators, andcaregivers were unaware of the group as-



Röder 2007 (Continued)

signment and could not make a distinctionbetween verum and placebo treatment.







Sanchez-Palacios 2001


Participants Country: SpainSetting: Specialist care centreNumber randomised: 40 participantsAge: AdultsGender: Male 16 and female 24Inclusion criteria: Symptoms of perennial rhinitis and/or asthma associated with catexposure, monosensitisation to cat, positive nasal challenge test to cat epitelia.Exclusion criteria: Polysensitised patients, previous course of immunotherapy, poor com-pliance suspicion.

Interventions SLIT: Active therapy contained an aqueous extract of the major cat allergen Fel d 1(CBF-Leti). Five vials were provided containing: 0.00032, 0.0016, 0.008, 0.04, 0.02and 1 HEP equivalent/mL. Saline solution, glycerine 50% and phenol 0.4% was usedas vehicle. SLIT was provided daily and kept under the tongue for 3 minutes. After 1year of treatment the cumulative dose was 3.6 µg of Fel d 1.Placebo: Saline solution, glycerine 50% and phenol 0.4%.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (red, itchy, watery eyes)Ocular medication scores (eye drops)

Notes Allergen: CatPotential conflicts of interest: Not declared

Risk of bias




Sanchez-Palacios 2001 (Continued)







Unclear risk No details were provided in the paper.



Smith 2004


Participants Country: United KingdomSetting: General practice settingNumber randomised: 180 participantsAge: AdultsGender: Male 48 and female 41 (per protocol population)Inclusion criteria: Adults (18 to 60 years) were eligible if their seasonal rhinitis wasnot well controlled in previous years, despite prescription of nasal steroids and/or oralantihistamines, together with evidence of grass pollen sensitisation (skin prick whealdiameter % 4 mm and IgE RAST class 2).Exclusion criteria: Exclusion criteria were perennial rhinitis, asthma (except for peakseasonal wheezing), other significant medical illness, anticipation of difficulty attendingfollow-up, treatment with beta-blockers or systemic corticosteroids, and pregnancy orplanned pregnancy.

Interventions SLIT: Each year, treatment started in February with increasing daily doses of grass pollenextract (orchard, meadow, rye, sweet vernal, and timothy grasses) followed by mainte-nance therapy until July 31. The extract was standardised in IR units: 100 IR/mL wasdefined as the concentration eliciting a mean skin prick wheal diameter of 7 mm in 30sensitised participants. The quantity 100 IR contained 24 µg Lol p 1 and 14 mg Dac µg5. Participants received increasing doses starting with 1 drop of 1 IR/mL and increasingto 20 drops of 100 IR/mL by day 14. Participants then switched to tablets (100 IR),using 1 tablet/d for 1 week, 2 tablets/d for a week, and then 3 tablets/d for 4 weeks.Subsequent maintenance therapy was given as tablets (3 times/wk for 17 weeks). Thecumulative annual dose was 26,100 IR (6264 mg Lol p 1 and 3654 mg Dac g 5).Placebo: Placebo tablets and drops were physically identical to active medication.



Smith 2004 (Continued)

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (itching, watery eyes)Conjunctival immediate allergen sensitivity

Notes Allergen: Grass mixOne group received active treatment for 2 years, 1 group received 1 year of active treat-ment and then placebo, and the third group received placebo in both years.Potential conflicts of interest: Supported by Stallergènes and one of the authors is linkedto Stallergènes France

Risk of bias




Allocation concealment (selection bias) Unclear risk Authors stated that groups were checkedfor homogeneity regarding demographics,symptom scores, and relevant clinical pa-rameters.


Low risk Investigators and participants were maskedto treatment assignment for the duration ofthe study. Placebo tablets and drops werephysically identical to active medication.





Torres-Lima 2002


Participants Country: United KingdomSetting: Specialist care centreNumber randomised: 56 participantsAge: Adults (21 to 53 years old)Gender: Male 32 and female 24Inclusion criteria: All participants gave a history of seasonal allergic rhinoconjunctivitis ofat least 2 years duration and a positive skin-prick test (weal diameter > 5 mm) to timothygrass pollen extract. Participants with mild seasonal asthma were included, provided their



Torres-Lima 2002 (Continued)

symptoms were controlled by inhaled beta 2-agonist alone.Exclusion criteria: Participants were excluded if they gave a clinical history of otherallergies, had received immunotherapy in the previous 5 years or had any other significantmedical illness. Allergy to cat and/or dog was an exclusion criteria only if participantshad daily contact with pets. Participants with chronic asthma were excluded.

Interventions SLIT: The immunotherapy treatment was Soluprick SQ (ALK Abelló), a standardisedextract of Phleum pratense (timothy grass pollen) diluted in 50% glycerol. The concen-tration of grass pollen allergen extract was 1 mg/mL. The duration of treatment was 12to 18 months. The treatment schedule comprised a 6-week up-dosing phase followedby daily maintenance treatment. In view of the high doses of allergen extract employed,up-dosing was supervised in hospital, in the presence of a physician, with availabilityof resuscitative measures. Maintenance doses were taken at home. Up-dosing involved3 visits per week, with 1 drop (25 µg of Phleum pratense extract) administered per visitin the first week, 2 drops in week 2 then 4, 7, 10 and 14 drops in weeks 3, 4, 5 and 6,respectively. The maintenance dose was 6 drops every day (4500 µg of Phleum pratenseextract per month), giving a cumulative monthly dose of major allergen (Phl p 5) ofapproximately 900 µg, equivalent to 40 to 50 times the amount contained in the usualmonthly maintenance injections via the subcutaneous route. Drops were kept under thetongue for 3 minutes before swallowing.Placebo: It was identical to the extract in appearance, presentation, taste and colour.

Outcomes Conjunctival immediate allergen sensitivity

Notes Allergen: Phleum pratensePotential Conflicts of interest: Supported by ALK-Abelló

Risk of bias



Low risk Randomisation to active or placebo treat-ment was performed by the manufacturerof the grass pollen vaccine using a systemof computer-generated random numbers inblocks of 12.



Low risk The treatment schedule and assessmentswere performed double-masked, with treat-ment allocations kept in sealed envelopesby the principal investigator.






Torres-Lima 2002 (Continued)


Troise 1995


Participants Country: ItalySetting: Specialist care centreNumber randomised: 31 participantsAge: AdultsGender: Male 12 and female 19Inclusion criteria: 1) Severe symptoms of rhinitis without asthmatic manifestations duringthe Parietaria pollen season for at least 2 consecutive years, 2) positive skin prick testonly to Parietaria judaica at the concentration of 100 BU/mL and 3) positive RAST forParietaria class III or more.Exclusion criteria: Participants were ineligible if they had a disease that could interferewith the evaluation of clinical symptoms, such as rhinitis medicamentosa, sinusitis orlarge obstructive nasal polyps; pregnancy or nursing; not taking adequate female con-traception, had serious cardiac, pulmonary, renal, hepatic, neurological or malignantdisease, or were travelling outside the pollen area for more than 1 week.

Interventions SLIT: Treatment was initiated in January 1991 before the Parietaria pollen season andcontinued for 10 months. Active therapy contained an aqueous extract of Parietariajudaica pollen in physiological saline and 50% glycerol preserved with 0.4% w/v phe-nol. The aqueous extract was provided in 5 vials (0 to 4) at fivefold increasing aller-gen concentrations from 0.008 up to 5 BU/mL in the highest-concentration vial. Theparticipants received increasing doses from each vial starting with 1 drop from vial 0and increasing by 1 drop every 2 days to 5 drops by the ninth and the tenth days. Thisschedule was repeated with the other vials, increasing by 1 drop daily to 5 drops by thefifth day. The duration of the build-up period was 30 days, followed by maintenancetherapy consisting of 5 drops from vial 4 taken on Monday, Wednesday and Friday.During the pollen season (April to August) drops were reduced to 3. A total dose of 105BU containing about 6.3 µg of the major allergen of P. judaica (Par j 1) was administeredto each participant on the active treatment for 10 months.Placebo: Consisted of saline solution in identical vials, with colour and similar taste tothe active product.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (itching and red eyes)Ocular medication scores (eye drops)

Notes Allergen: Parietaria judaicaPotential conflicts of interest: One of the authors is linked to Neo-Abelló, Milan, Italy

Risk of bias



Troise 1995 (Continued)




Allocation concealment (selection bias) Unclear risk It was not specified in the paper.




Low risk Participants lost to follow-up or excludedwere accounted for along with participantsfollowed to designated follow-up periods.The specified outcomes in the methodol-ogy were reported in the results section.



Valovirta 2006


Participants Country: FinlandSetting: Specialist care centreNumber randomised: 98 participantsAge: ChildrenGender: ITT: Male 31 and female 25 (dose 2 and placebo)Inclusion criteria: Age 5 to 14 years; clinical history of tree pollen-induced allergicrhinoconjunctivitis with/without seasonal asthma for at least 2 years; Positive specificIgE to tree mix and either 1 of Betula verrucosa, Corylus avellana and Alnus glutinosa;Positive CPT # 100 000 SQ-U/ml to tree mix; Bronchial provocation test with metha-choline PD20 % 150 µg; Tree pollen allergy responsible for the majority of clinicalsymptoms.Exclusion criteria: Perennial allergic symptoms; Clinically important symptoms of foodallergy unless they are unsymptomatic with elimination diet; Clinically important historyof house dust mite and/or mould allergy; Positive SPT % 3 mm to Dermatophagoidespteronyssinus, Dermatophagoides farinae and Cladosporium herbarium, Alternaria al-ternata; Daily contact with any pet to which the patient is sensitised; Any other clinicallysignificant disease (as judged by the investigator) that might affect the outcome of thetrial or the patient’s health; Treatment with beta-blockers or ACE inhibitors; Non allergicchronic rhinitis or sinusitis; Previous immunotherapy with any tree pollen extracts withinthe last 5 years; Treatment with long-acting beta 2-agonist and/or antileukotrienes; FEV1



Valovirta 2006 (Continued)

< 70% and PEF < 80% of predicted normal value; Severe atopic dermatitis; Seasonalasthma requiring more than 400 µg budesonide/day, 400 µg beclomethasone / day, 200µg fluticasone/day; Nasal corticosteroid; cromones for asthma.

Interventions SLIT: The allergen extract used for SLIT was a tree pollen extract of SQ-standardised B.verrucosa (birch), C. avellana (hazel) and A. glutinosa (alder). An extract concentration of1,000,000 SQ-U/ml (100 HEP) contains: 1.00 mg B. verrucosa, 1.40 mg C. avellana and1.00 mg A. glutinosa corresponding to a major allergen content of 150 µg (Bet v 1/Aln g1/Cor a 1). Sublingual immunotherapy was carried out at home. The study medicationwas a fluid in multiple-use vials. Each dose consisted of 10 drops (400 µl). Treatmentwas administered 5 times per week with a 5-week up-dosing phase and a maintenanceperiod of up to 18 months. The dose was administered sublingually and kept under thetongue for 3 minutes and then swallowed. The children were randomised equally to 1 ofthe 3 following groups: (i) Dose group 1: the active study medication for dose group 1was, for the up-dosing - phase, tree pollen extract in the concentrations 150, 400, 1500,4000 and 12,000 SQ-U/ml and, for maintenance phase, a concentration of 12,000 SQ-U/ml. The accumulated weekly dose corresponded to 24,000 SQ-U or 3.6 µg majorallergen Bet v 1/Aln g 1/Cor a 1. (ii) Dose group 2: the active study medication forthis group was, for the up-dosing phase, tree pollen extract in the concentrations 1500,4000, 12,000, 35,000 and 100,000 SQ-U/ml and, for maintenance, a concentration of100 000 SQ-U/ml. The accumulated weekly dose corresponded to 200,000 SQ-U or30 µg major allergen Bet v 1/Aln g 1/Cor a 1.Placebo: The placebo medication was, for the up-dosing and maintenance phase, a diluentcontaining 50% glycerol and 50% saline buffer.


Notes Allergen: Tree pollen (Betula verrucosa, Corylus avellana and Alnus glutinosa)Eighty-eight (32 in dose group 1, 27 in dose group 2 and 29 in the placebo group) wereincluded in the efficacy analysesPotential conflicts of interest: Two of the authors are linked to ALK-Abelló

Risk of bias






Low risk The study was conducted under double-masked conditions. There was no differ-ence in colour and viscosity between thestudy drug and placebo. All masking pro-cedures were performed by the Quality As-surance Department at ALK-Abelló A/S.



Valovirta 2006 (Continued)





Vervloet 2007


Participants Country: FranceSetting: Specialist care centreNumber randomised: 76 participantsAge: Adults (19 to 60 years old)Gender: Male 39 and female 37Inclusion criteria: Participants had to have typical symptoms of rhinoconjunctivitis, pos-sibly associated with moderate asthma, during the cypress pollen season (January, Febru-ary, March). Sensitisation was confirmed by positive skin prick test to C. sempervirensor C. arizonica and to J. ashei extracts and serum specific antibody levels to J. ashei andCupressus greater than or equal to class 2 as determined by CAP.Exclusion criteria: Perennial allergic rhinoconjunctivitis to mites or cockroaches; severeintermittent or persistent asthma; participants sensitised to cat or dog dander and livingwith pets at home. Patients previously treated with immunotherapy or beta-blockers wereexcluded. Other exclusion criteria were the known contraindications to immunotherapyaccording to the EAACI guidelines.

Interventions SLIT: A purified standardised J. ashei extract was manufactured by Stallergènes (Antony,France). The Jun a 1 major allergen content was 76 µg/ml of the 100 IR allergen extract.Sublingual therapy was graded in a single concentration of 300 IR/ml (equivalent to 30histamine equivalent potency, HEP) in 50% glycerol aqueous solution. The treatmentwas started on day 1 with a titration within 90 minutes (30-90-150-300 IR). Maintenancetreatment (300 IR) was given once a day before breakfast for 120 days in a one-offtreatment. This daily dose in maintenance treatment corresponded to 228 µg Jun a 1. Inthe 2001 protocol, indwelling intravenous lines were used in all cases during the ultra-rush procedure.Placebo: Placebo consisted of 50% glycerol aqueous solution.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (itchy, watery and red eyes)Ocular medication scores (eye drops)

Notes Allergen: Juniperus asheiIn order to analyse about 80 participants, participants were enrolled in the trial in both2001 and 2002.Potential Conflicts of interest: Supported by Stallergènes



Vervloet 2007 (Continued)

Risk of bias



Low risk Randomisation in blocks was used.








Voltolini 2001


Participants Country: ItalySetting: Specialist care centreNumber randomised: 30 participantsAge: Adults (17 to 64 years old)Gender: Male 11 and female 19Inclusion criteria: Clinical history of at least 2 years of seasonal rhinoconjunctivitis, withor without intermittent to moderate persistent asthma (21); sensitisation to Betulaceae/Corylaceae pollens confirmed by in vivo (SPT) and in vitro (RAST) positive diagnosis;age ranging from 12 to 65 years.Exclusion criteria: Chronic asthma; nasal polyps; previous treatment with specific im-munotherapy within the last 5 years; sensitisation to other inhalant allergens; pregnancyin progress or already planned; chronic or recurrent inflammation of the oral mucosa.

Interventions SLIT: The active specific immunotherapy consisted of a mixture 1:1:1 of 3 biologicallystandardised pollen extracts (alder, birch, hazel), graded in 6 strengths: 0.04, 0.2, 1,5, 25 and 100 BU/mL in glycerosaline solution. For the birch extract, 100 BU/mLcorrespond to 66 µg/mL of the major allergen Bet v 1. A rush pre-seasonal treatmentschedule was followed. Drops were taken sublingually twice a day, morning and eveningfor 18 days starting from 1 drop of strength 0.04 BU/mL up to 5 drops of the samevial. The same procedure was repeated to reach the top dose of 5 drops of strength 100



Voltolini 2001 (Continued)

BU/mL. Each allergen dose had to be kept in the mouth for at least 2 minutes and thenanything remaining in the mouth had to be swallowed. The treatment started in themiddle of December 1997 so that the maximum dose was reached before the beginningof the pollen season and repeated 5 days a week (Monday to Friday) for 1 month. A co-seasonal maintenance treatment followed, at a dosage of 5 drops of strength 25 BU/mL3 times a week until the end of the pollen season. The cumulative dosage received byeach participant was therefore 819 BU in 5 months on average. For birch extract, thisamount corresponds to around 445 µg of the major allergen Bet v 1.Placebo: Placebo was prepared as saline solution in vials with exactly the same appearance,colour and taste, but without allergens. All vials contained 50 % glycerine (V/V) and0,3% phenol (W/V).

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (itching and red eyes)Ocular medication scores (eye drops)

Notes Allergen: Tree pollens - Mix of Betulaceae/Corylaceae (alder, birch and hazel)The study followed a double-masked, placebo controlled design during the first year andan open-controlled design during the second yearPotential conflicts of interest: Two of the authors are linked to ALK-Abelló

Risk of bias






Low risk Investigators and participants were maskedto treatment assignment for the durationof the study. Placebo was prepared as salinesolution in vials with exactly the same ap-pearance, colour and taste, but without al-lergens, in order to guarantee the double-masked design of the trial.







Vourdas 1998


Participants Country: GreeceSetting: Specialist care centreNumber randomised: 66 participantsAge: ChildrenGender: Male 49 and female 17Inclusion criteria: Participants with a positive history of rhinoconjunctivitis and/or mildasthma due to sensitisation to olive pollen proved by positive skin prick tests and positiveRAST class II and above were included.Exclusion criteria: Participants who had uncontrolled asthma or symptomatic polysensi-tisation, or who were taking beta-blockers or retard corticosteroids were excluded.

Interventions SLIT: The study ran for 2 consecutive years (October 1994 to October 1996), thesublingual therapy being administered pre- and co-seasonally from January to July eachyear. The active treatment was a standardised olive pollen extract (Stallergenes SA). Themajor allergen Ole e 1 was 13.5 ig/ml (100 IR/ml). Four concentrations of the allergenwere used: 1, 10, 100, and 300 IR/ml. Participants received drops to be taken eachmorning sublingually and held under the tongue for 2 minutes before being swallowed.The treatment was started in January 1995 with 2 drops of the lowest concentration (1IR/ml), increasing by 2 drops per day up to a maximum of 10 drops/day. The treatmentcontinued with 2 drops of the next concentration (10 IR/ml), increasing by 2 drops perday up to 10 drops/day, and then progressing in a similar way from 2 to 20 drops of thenext concentration (100 IR/ml) and then of the highest concentration (300 IR/ml). Themaintenance dose was 20 drops of 300 IR/ml daily for 5 months. In July, the treatmentwas stopped until the next January. The same schedule was used for the second seasonof the trial. The cumulative dose of allergenic extract received by each patient was 30000 IR per year (300 times higher than in parenteral specific immunotherapy). Thecumulative dose of major allergen Ole e 1 was 4.05 mg/year.Placebo: The placebo was a glycerinated phenolated saline solution with an appearancesimilar to that of the active agent.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (red, itchy and watery eyes)

Notes Allergen: Olea europaeaPotential conflicts of interest: Three of the authors are linked to Stallergènes France

Risk of bias







Vourdas 1998 (Continued)


Low risk Investigators and participants were maskedto treatment assignment for the duration ofthe study. The placebo was a glycerinatedphenolated saline solution with an appear-ance similar to that of the active agent.





Wahn 2009


Participants Country: France, Spain, Germany, Poland and Denmark.Setting: 29 specialist care centres in 5 countriesNumber randomised: 278 participantsAge: ChildrenGender: Female to male: 36% to 64%Inclusion criteria: Children and adolescents 5 to 17 years of age. All participants hadgrass pollen-related moderate-to-severe allergic rhinoconjunctivitis for at least 2 yearsconfirmed by means of a positive skin prick test response (wheal diameter, > 3 mm) anda timothy grass pollen-specific IgE level of at least class 2 (% 0.7 kU/L); had a score ofat least 12 of a possible 18 on the retrospective rhinoconjunctivitis total symptom score,determined on the basis of the most severe symptoms during the previous pollen season.The SPT included grasses and a panel of the most commons allergens in each country.Children with asthma requiring treatment only with beta 2-agonists could be included.Exclusion criteria: Participants with symptoms of rhinoconjunctivitis during the grasspollen season caused by sensitisation to allergens other than grass pollen, including peren-nial allergens causing rhinitis symptoms, asthma requiring treatment other than beta2 inhaled agonists; participants who had received any desensitisation therapy for grasspollen; and the usual contraindications for specific immunotherapy, such as concomitantbeta-blocker therapy, severe and/or stable asthma, severe immune deficiency or autoim-mune disease, or malignancies.

Interventions SLIT: SLIT tablets containing freeze-dried allergen extract of 5 grass pollens (orchard,meadow, perennial rye, sweet vernal, and timothy grasses) at a dose of 300 IR were usedfor the study. A 300-IR tablet corresponded to approximately 20 mg of the group 5major allergens.Placebo: The placebo tablet matched the active treatment in size, shape, and colour butcontained no active ingredients. Excipients were identical to those in the active treatment



Wahn 2009 (Continued)

tablets, with the addition of caramel and quinoline yellow.

Outcomes Total ocular symptom scoresIndividual ocular symptom scores (red, itchy and watery eyes)

Notes Allergen: Grass pollenPotential Conflicts of interest: Supported by Stallergènes

Risk of bias



Low risk The randomisation list was stratified bystudy centre and organised in blocks.



Low risk Investigators and participants were maskedto treatment assignment for the durationof the study. Excipients used in both activeand placebo tablets include lactose, sodiumstearate, and sodium croscarmellose.





Wuthrich 2003


Participants Country: SwitzerlandSetting: Five specialist care centresNumber randomised: 28 participantsAge: Children (4 to 11 years old)Gender: Male 20 and female 8Inclusion criteria: History of seasonal rhinoconjunctivitis in the months of May to July(grass pollen season) with or without mild asthma and positive skin prick tests and/orspecific IgE (RAST/CAP) to grass pollen.Exclusion criteria: History of allergic rhinitis/asthma during the spring (March to Aprilcorresponding to tree pollinosis) and/or perennial rhinitis or asthma or severe atopicdermatitis.



Wuthrich 2003 (Continued)

Interventions SLIT: The schedule of treatment included the daily administration of the drops untilthe maintenance dose was reached, beginning with 1 drop from vial 0 on the first dayand second day, increasing by 1 drop every 2 days, and culminating with 5 drops onthe ninth and tenth days. The administration from the vials 1, 2, 3 and 4 were begunwith 1 drop followed by a daily increase of 1 drop until reaching 5 drops on the fifthday. The maintenance dose of 5 drops from vial 4, corresponding to 0.5 µg of the majorgrass allergen group 5, was administered 3 times a week until the end of July 2000. Thegrass mix included Dactylis glomerata, Festuca pratensis, Lolium perenne, Phleum pratenseand Poa pratensis. In the build-up phase (30 days), the cumulative dose of major allergenwas 1.88 µg, whereas in the maintenance phase the cumulative dose/month of majorallergen was 6 µg. In the first year, the cumulative dose was 67.88 µg and in the secondyear 139.88 µg of the major allergen in total (67.88 + (6 x 12 months)).Placebo: Identical glycerosaline phenolated solution.

Outcomes Conjunctival immediate allergen sensitivity

Notes Allergen: Grass mixPotential Conflicts of interest: Not declared

Risk of bias



Unclear risk Participants were randomised.







Other bias Unclear risk Small number of participants across eachtrial group.



Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Alvarez-Cuesta 2007 Ocular outcomes were not evaluated

Amar 2009 Data not suitable for analysis

Bahceciler 2001 Ocular outcomes were not evaluated

Bahceciler 2005 Open trial, not placebo controlled

Boquete 2006 Study designed to evaluate safety

Bordignon 2003 Not placebo controlled, other outcomes investigated

Brown 2001 Editorial

Burastero 2008 Open trial, not placebo controlled

Caffarelli 2000 Intervention classified as oral immunotherapy

Ciprandi 2007 Open trial, not placebo controlled

Clavel 1996 Data presented as full paper in 1998

Clavel 1998 Data not available

Di Rienzo 2006 Ocular outcomes were not evaluated

Didier 2009 Data already presented elsewhere

Drachenberg 2001 Ocular outcomes were not evaluated

Durham 2007 Data was already presented in Dahl 2006b

Durham 2010 Data already presented elsewhere

Esch 2008 Data not available

Grosclaude 2002 Study designed to evaluate safety

Guez 2000 Ocular outcomes were not evaluated

Horak 2008 Data were already presented in Didier 2007

Horak 2009 Data already presented elsewhere

Horak 2009a No natural allergen exposure



(Continued)

Hordijk 1998 Data not available

Horiguchi 2008a Study single masked

Horiguchi 2008b Not placebo controlled

Ippoliti 2003 Ocular outcomes were not evaluated

Kleine-Tebbe 2007 Review

Lombardi 2005 Double-intervention

Lue 2006 Ocular outcomes were not evaluated

Maestrelli 2004 Subcutaneous immunotherapy

Malling 2009 Data already presented elsewhere

Marcucci 2001 Not placebo controlled

Marcucci 2003 Ocular outcomes were not evaluated

Marcucci 2005a Not placebo controlled

Marcucci 2005b Ocular outcomes were not evaluated

Maria 2004 Not placebo controlled

Mitsch 1996 Open study

Mungan 1999 Single-masked study

Mösges 2007 Data not available

Nelson 1993 Data not available

Niu 2006 Data not available

Okubo 2008 Data not available

Pajno 2000 Ocular outcomes were not evaluated

Pajno 2003 Double intervention

Peter 2009 Other outcomes were evaluated

Potter 2007 Data not available



(Continued)

Quirino 1996 Placebo controlled group not included

Radu 2007 Single-masked study

Roberta 2009a Different study design

Roberta 2009b Not placebo controlled

Rossi 2005 Not randomised, not placebo controlled

Rukhadze 2008 Not randomised, not placebo controlled

Sabbah 1994 Data not available

Scadding 1986 Crossover design

Sieber 2009 Not placebo controlled

Stelmach 2009 Differences in inclusion criteria

Stosovic 2008 Not placebo controlled

Tari 1990 Data not available

Tonnel 2004 Data not available

Troise 2009 Data not available

Tseng 2008 Data not available

Ventura 2009 Design differences

Wessner 2001 Data not available

Worm 2006 Ocular outcomes were not evaluated

Worm 2009 Data already presented elsewhere

Yuksel 1999 Single-masked study



D A T A A N D A N A L Y S E S

Comparison 1. Sublingual immunotherapy versus placebo

Outcome or subgroup titleNo. ofstudies

No. ofparticipants Statistical method Effect size

1 Total ocular symptom scores 36 3399 Std. Mean Difference (IV, Random, 95% CI) -0.41 [-0.53, -0.28]2 Itchy/Gritty eyes 28 3020 Std. Mean Difference (IV, Random, 95% CI) -0.31 [-0.42, -0.20]3 Watery eyes 21 2641 Std. Mean Difference (IV, Random, 95% CI) -0.23 [-0.34, -0.11]4 Red eyes 20 1211 Std. Mean Difference (IV, Fixed, 95% CI) -0.33 [-0.45, -0.22]5 Swollen eyes 2 132 Std. Mean Difference (IV, Random, 95% CI) -0.23 [-1.19, 0.72]6 Eye drops 13 1038 Std. Mean Difference (IV, Fixed, 95% CI) -0.10 [-0.22, 0.03]

7 Combined symptom-medicationscores

3 351 Std. Mean Difference (IV, Random, 95% CI) -0.21 [-0.55, 0.13]

8 Conjunctival immediate allergensensitivity

4 250 Std. Mean Difference (IV, Random, 95% CI) 0.35 [0.00, 0.69]

9 Total ocular symptom scores:Seasonal and perennial

36 3399 Std. Mean Difference (IV, Random, 95% CI) -0.40 [-0.52, -0.28]

9.1 Seasonal 30 3180 Std. Mean Difference (IV, Random, 95% CI) -0.38 [-0.50, -0.25]9.2 Perennial 6 219 Std. Mean Difference (IV, Random, 95% CI) -0.52 [-1.05, 0.01]

10 Total ocular symptom scores:Adults and children


10.1 Children 9 857 Std. Mean Difference (IV, Random, 95% CI) -0.27 [-0.46, -0.07]10.2 Adults 27 2542 Std. Mean Difference (IV, Random, 95% CI) -0.48 [-0.63, -0.32]

11 Total ocular symptom scores:Publication year


11.1 1994 - 1999 11 451 Std. Mean Difference (IV, Random, 95% CI) -0.65 [-0.98, -0.33]11.2 2000 - 2005 10 575 Std. Mean Difference (IV, Random, 95% CI) -0.43 [-0.73, -0.13]11.3 2006 - 2009 15 2373 Std. Mean Difference (IV, Random, 95% CI) -0.31 [-0.45, -0.17]

12 Total ocular symptom scores:Treatment > 12 months


12.1 12 months or less 26 2888 Std. Mean Difference (IV, Random, 95% CI) -0.40 [-0.53, -0.27]12.2 13 months or more 10 511 Std. Mean Difference (IV, Random, 95% CI) -0.43 [-0.76, -0.10]

13 Total ocular symptom scores:Fixed-effects model

36 3399 Std. Mean Difference (IV, Fixed, 95% CI) -0.37 [-0.43, -0.30]



Analysis 1.1. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 1 Total ocular symptomscores.

Review: Sublingual immunotherapy for treating allergic conjunctivitis

Comparison: 1 Sublingual immunotherapy versus placebo

Outcome: 1 Total ocular symptom scores

Study or subgroup Sublingual Immunotherapy Placebo Std. Mean Difference Weight Std. Mean Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Feliziani 1995 18 1.3 (0.3) 16 2.1 (0.5) 1.6 % -1.92 [ -2.75, -1.09 ]

Passalacqua 1998 10 12.7 (4.6) 10 28 (11.1) 1.1 % -1.72 [ -2.78, -0.66 ]

Ariano 2001 10 0.7 (0.48) 10 1.9 (0.82) 1.1 % -1.71 [ -2.77, -0.65 ]

Passalacqua 1999 15 27.2 (12.6) 15 45.3 (16.8) 1.7 % -1.19 [ -1.97, -0.40 ]

Mortemousque 2003 26 5.76 (0.9) 19 7 (1.33) 2.2 % -1.11 [ -1.75, -0.47 ]

Palma-Carlos 2006 17 22.85 (27.02) 16 58.29 (41.21) 1.9 % -1.00 [ -1.73, -0.27 ]

Panzner 2008 20 60.2 (81.25) 15 185.67 (183.85) 2.0 % -0.91 [ -1.62, -0.20 ]

Casanovas 1994 9 1.29 (0.73) 6 2.5 (1.96) 1.0 % -0.85 [ -1.94, 0.24 ]

Troise 1995 15 43 (50) 16 79 (40) 1.9 % -0.78 [ -1.51, -0.04 ]

Khinchi 2004 18 0.87 (0.576) 19 1.32 (0.75) 2.1 % -0.66 [ -1.32, 0.01 ]

Cao 2007 29 1.66 (1.03) 37 2.43 (1.39) 2.9 % -0.61 [ -1.11, -0.11 ]

Purello-D’ Ambrosio 1999 14 158 (174) 16 268 (202) 1.9 % -0.56 [ -1.30, 0.17 ]

Dahl 2006b 282 0.7 (0.6) 286 1.1 (0.8) 5.2 % -0.56 [ -0.73, -0.40 ]

Voltolini 2001 15 34.6 (39) 15 68 (75) 1.9 % -0.54 [ -1.27, 0.19 ]

Wahn 2009 131 0.77 (1.016) 135 1.34 (1.194) 4.7 % -0.51 [ -0.76, -0.27 ]

Dubakiene 2003 47 0.24 (0.27) 53 0.41 (0.39) 3.6 % -0.50 [ -0.90, -0.10 ]

Sanchez-Palacios 2001 20 2 (2) 20 3.5 (4) 2.3 % -0.46 [ -1.09, 0.16 ]

Andre 2003 26 1.11 (0.91) 48 1.69 (1.48) 3.0 % -0.44 [ -0.92, 0.04 ]

Vourdas 1998 33 0.199 (0.466) 31 0.56 (1.259) 2.9 % -0.38 [ -0.88, 0.11 ]

Didier 2007 136 0.95 (1.1) 148 1.4 (1.24) 4.7 % -0.38 [ -0.62, -0.15 ]

Pradalier 1999 62 1.06 (1.02) 61 1.55 (1.53) 3.9 % -0.38 [ -0.73, -0.02 ]

de Blay 2007 53 7.79 (9.28) 51 11.18 (10.82) 3.6 % -0.33 [ -0.72, 0.05 ]

Bufe 2008 117 0.91 (0.95) 121 1.23 (1.14) 4.6 % -0.30 [ -0.56, -0.05 ]

Valovirta 2006 32 0.8 (1.2) 33 1.1 (0.9) 3.0 % -0.28 [ -0.77, 0.21 ]

Horak 1998 21 2 (3.46) 20 2.9 (4.12) 2.3 % -0.23 [ -0.85, 0.38 ]

-4 -2 0 2 4

Favours SLIT Favours Placebo

(Continued . . . )



(. . . Continued)Study or subgroup Sublingual Immunotherapy Placebo Std. Mean Difference Weight Std. Mean Difference


Bowen 2004 27 1.96 (1.9) 29 2.38 (1.92) 2.8 % -0.22 [ -0.74, 0.31 ]

La Rosa 1999 16 0.23 (0.445) 17 0.35 (0.629) 2.0 % -0.21 [ -0.90, 0.47 ]

Dahl 2006a 61 0.75 (0.78) 32 0.88 (0.68) 3.4 % -0.17 [ -0.60, 0.26 ]

Ott 2008 123 1.28 (1.77) 60 1.51 (1.93) 4.2 % -0.13 [ -0.43, 0.18 ]

Durham 2006 141 0.74 (0.78) 136 0.81 (0.75) 4.7 % -0.09 [ -0.33, 0.14 ]

Vervloet 2007 22 1.14 (1.14) 21 1.24 (1.4) 2.4 % -0.08 [ -0.68, 0.52 ]

Moreno-Ancillo 2007 51 0.48 (0.39) 49 0.46 (0.31) 3.6 % 0.06 [ -0.34, 0.45 ]

Hirsch 1997 15 0.36 (0.69) 15 0.31 (0.62) 1.9 % 0.07 [ -0.64, 0.79 ]

Rolinck-Werninghaus 2004 39 6.83 (13.63) 38 5.15 (9.81) 3.2 % 0.14 [ -0.31, 0.59 ]

Smith 2004 45 1.09 (1.224) 51 0.86 (0.748) 3.5 % 0.23 [ -0.18, 0.63 ]

Aydogan 2007 9 0.22 (0.43) 9 0.01 (0.02) 1.3 % 0.66 [ -0.30, 1.61 ]

Total (95% CI) 1725 1674 100.0 % -0.41 [ -0.53, -0.28 ]Heterogeneity: Tau2 = 0.07; Chi2 = 85.79, df = 35 (P<0.00001); I2 =59%

Test for overall effect: Z = 6.53 (P < 0.00001)

-4 -2 0 2 4




Analysis 1.2. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 2 Itchy/Gritty eyes.



Outcome: 2 Itchy/Gritty eyes



Feliziani 1995 18 0.5 (0.2) 16 0.9 (0.4) 1.8 % -1.26 [ -2.00, -0.51 ]

Panzner 2008 20 20.7 (24.31) 15 57.2 (48.73) 1.9 % -0.97 [ -1.68, -0.26 ]

Cao 2007 29 0.72 (0.45) 37 1.32 (0.74) 3.1 % -0.94 [ -1.46, -0.43 ]

Troise 1995 15 20 (23) 16 37 (22) 1.8 % -0.74 [ -1.47, -0.01 ]

Passalacqua 1999 15 16.8 (6) 15 22 (9.1) 1.8 % -0.66 [ -1.39, 0.08 ]

Voltolini 2001 15 16.4 (20) 15 32 (28) 1.8 % -0.62 [ -1.36, 0.11 ]

Sanchez-Palacios 2001 20 2.2 (1) 20 3.2 (2) 2.3 % -0.62 [ -1.26, 0.02 ]


Wahn 2009 131 0.51 (0.595) 135 0.85 (0.699) 6.4 % -0.52 [ -0.77, -0.28 ]

Dahl 2006b 282 0.46 (0.38) 286 0.66 (0.49) 7.6 % -0.46 [ -0.62, -0.29 ]

Didier 2007 136 0.56 (0.61) 148 0.8 (0.706) 6.5 % -0.36 [ -0.60, -0.13 ]

Ott 2008 123 0.81 (0.68) 60 1.04 (0.63) 5.3 % -0.34 [ -0.66, -0.03 ]

de Blay 2007 53 0.77 (0.97) 50 1.12 (1.1) 4.3 % -0.34 [ -0.72, 0.05 ]

Andre 2003 26 0.51 (0.46) 48 0.67 (0.53) 3.4 % -0.31 [ -0.79, 0.17 ]

Vourdas 1998 33 0.1 (0.23) 31 0.21 (0.457) 3.3 % -0.31 [ -0.80, 0.18 ]

Pradalier 1999 62 0.47 (0.44) 61 0.62 (0.55) 4.7 % -0.30 [ -0.66, 0.06 ]

Dahl 2006a 61 0.48 (0.44) 32 0.61 (0.47) 3.9 % -0.29 [ -0.72, 0.14 ]

La Rosa 1999 16 0.11 (0.199) 17 0.22 (0.49) 2.0 % -0.28 [ -0.97, 0.40 ]

Bowen 2004 27 0.82 (0.77) 29 0.99 (0.67) 3.0 % -0.23 [ -0.76, 0.29 ]

Horak 1998 21 0.96 (1.38) 20 1.32 (1.65) 2.4 % -0.23 [ -0.85, 0.38 ]

Durham 2006 141 0.48 (0.44) 136 0.56 (0.46) 6.5 % -0.18 [ -0.41, 0.06 ]

Dubakiene 2003 47 0.096 (0.336) 53 0.16 (0.485) 4.3 % -0.16 [ -0.55, 0.24 ]

Rder 2007 91 0.65 (0.5) 77 0.66 (0.4) 5.5 % -0.02 [ -0.33, 0.28 ]


Smith 2004 46 0.554 (0.541) 51 0.5 (0.349) 4.2 % 0.11 [ -0.29, 0.51 ]

Vervloet 2007 22 0.43 (0.47) 21 0.37 (0.5) 2.5 % 0.12 [ -0.48, 0.72 ]

-4 -2 0 2 4

Favours SLIT Favours control

(Continued . . . )





Passalacqua 2006 28 0.4 (0.3) 28 0.3 (0.3) 3.0 % 0.33 [ -0.20, 0.86 ]

Aydogan 2007 9 0.28 (0.48) 9 0 (0.013) 1.1 % 0.77 [ -0.19, 1.74 ]

Total (95% CI) 1540 1480 100.0 % -0.31 [ -0.42, -0.20 ]Heterogeneity: Tau2 = 0.03; Chi2 = 50.23, df = 27 (P = 0.004); I2 =46%


-4 -2 0 2 4

Favours SLIT Favours control

Analysis 1.3. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 3 Watery eyes.



Outcome: 3 Watery eyes



Panzner 2008 20 13.8 (22.08) 15 44.13 (49.55) 2.2 % -0.81 [ -1.51, -0.12 ]

Andre 2003 26 0.25 (0.24) 48 0.49 (0.49) 3.8 % -0.56 [ -1.05, -0.08 ]

Dahl 2006b 282 0.22 (0.28) 286 0.39 (0.4) 10.3 % -0.49 [ -0.66, -0.32 ]

Wahn 2009 131 0.26 (0.493) 135 0.49 (0.574) 8.2 % -0.43 [ -0.67, -0.19 ]

Pradalier 1999 62 0.27 (0.32) 61 0.43 (0.54) 5.7 % -0.36 [ -0.72, 0.00 ]

Didier 2007 136 0.39 (0.554) 148 0.59 (0.627) 8.4 % -0.34 [ -0.57, -0.10 ]

Sanchez-Palacios 2001 20 2.3 (3) 20 3 (1) 2.6 % -0.31 [ -0.93, 0.32 ]

Vervloet 2007 22 0.24 (0.36) 21 0.36 (0.52) 2.8 % -0.26 [ -0.87, 0.34 ]

Bowen 2004 27 0.57 (0.58) 29 0.73 (0.65) 3.4 % -0.26 [ -0.78, 0.27 ]

Dubakiene 2003 47 0.014 (0.132) 53 0.09 (0.373) 5.0 % -0.25 [ -0.64, 0.14 ]

Cao 2007 29 0.66 (0.6) 37 0.81 (0.65) 3.8 % -0.24 [ -0.72, 0.25 ]

Horak 1998 21 0.51 (1.11) 20 0.8 (1.43) 2.7 % -0.22 [ -0.84, 0.39 ]

Vourdas 1998 33 0.061 (0.163) 31 0.12 (0.412) 3.8 % -0.20 [ -0.69, 0.29 ]

Ott 2008 123 0.37 (0.67) 60 0.49 (0.58) 6.6 % -0.19 [ -0.50, 0.12 ]

-4 -2 0 2 4


(Continued . . . )





de Blay 2007 53 0.42 (0.75) 50 0.56 (0.84) 5.2 % -0.17 [ -0.56, 0.21 ]

La Rosa 1999 16 0.04 (0.082) 17 0.05 (0.112) 2.3 % -0.10 [ -0.78, 0.58 ]

Dahl 2006a 61 0.26 (0.39) 32 0.27 (0.31) 4.5 % -0.03 [ -0.46, 0.40 ]

Durham 2006 141 0.25 (0.38) 136 0.25 (0.34) 8.4 % 0.0 [ -0.24, 0.24 ]


Smith 2004 46 0.27 (0.367) 51 0.19 (0.214) 4.9 % 0.27 [ -0.13, 0.67 ]

Aydogan 2007 9 0.15 (0.32) 9 0.02 (0.04) 1.3 % 0.53 [ -0.41, 1.47 ]

Total (95% CI) 1344 1297 100.0 % -0.23 [ -0.34, -0.11 ]Heterogeneity: Tau2 = 0.02; Chi2 = 34.39, df = 20 (P = 0.02); I2 =42%

Test for overall effect: Z = 3.95 (P = 0.000077)

-4 -2 0 2 4


Analysis 1.4. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 4 Red eyes.



Outcome: 4 Red eyes


N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Passalacqua 1999 15 12 (7.1) 15 26 (12.1) 2.1 % -1.37 [ -2.18, -0.57 ]

Panzner 2008 20 16.9 (31.29) 15 51.47 (51.66) 2.7 % -0.82 [ -1.52, -0.12 ]

Sanchez-Palacios 2001 20 2 (1) 20 4.8 (5) 3.2 % -0.76 [ -1.41, -0.12 ]

Troise 1995 15 23 (25) 16 42 (24) 2.5 % -0.76 [ -1.49, -0.02 ]

Feliziani 1995 18 0.8 (0.5) 16 1.2 (0.7) 2.8 % -0.65 [ -1.34, 0.04 ]

Voltolini 2001 15 18.2 (22) 15 34 (32) 2.5 % -0.56 [ -1.29, 0.17 ]

Vourdas 1998 33 0.039 (0.125) 31 0.23 (0.526) 5.4 % -0.50 [ -0.99, 0.00 ]


Ott 2008 123 0.4 (0.66) 60 0.71 (0.64) 13.7 % -0.47 [ -0.78, -0.16 ]

-4 -2 0 2 4


(Continued . . . )





Andre 2003 26 0.35 (0.36) 48 0.52 (0.52) 5.8 % -0.36 [ -0.84, 0.12 ]

Pradalier 1999 62 0.33 (0.41) 61 0.5 (0.53) 10.5 % -0.36 [ -0.71, 0.00 ]

Cao 2007 29 0.24 (0.43) 37 0.38 (0.48) 5.6 % -0.30 [ -0.79, 0.19 ]

Dubakiene 2003 47 0.049 (0.256) 53 0.13 (0.451) 8.6 % -0.22 [ -0.62, 0.17 ]

Horak 1998 21 0.53 (1.13) 20 0.78 (1.37) 3.5 % -0.20 [ -0.81, 0.42 ]

de Blay 2007 53 0.43 (0.69) 50 0.54 (0.84) 8.9 % -0.14 [ -0.53, 0.24 ]

Bowen 2004 27 0.57 (0.64) 29 0.66 (0.7) 4.9 % -0.13 [ -0.66, 0.39 ]

Vervloet 2007 22 0.47 (0.53) 21 0.5 (0.63) 3.7 % -0.05 [ -0.65, 0.55 ]

La Rosa 1999 16 0.09 (0.227) 17 0.08 (0.175) 2.9 % 0.05 [ -0.63, 0.73 ]


Aydogan 2007 9 0.3 (0.54) 9 0.02 (0.04) 1.5 % 0.70 [ -0.26, 1.66 ]

Total (95% CI) 624 587 100.0 % -0.33 [ -0.45, -0.22 ]Heterogeneity: Chi2 = 26.16, df = 19 (P = 0.13); I2 =27%


-4 -2 0 2 4


Analysis 1.5. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 5 Swollen eyes.



Outcome: 5 Swollen eyes



Panzner 2008 20 8.8 (15.94) 15 32.87 (43.21) 45.6 % -0.77 [ -1.46, -0.07 ]

Smith 2004 46 0.246 (0.418) 51 0.17 (0.27) 54.4 % 0.21 [ -0.19, 0.61 ]

Total (95% CI) 66 66 100.0 % -0.23 [ -1.19, 0.72 ]Heterogeneity: Tau2 = 0.40; Chi2 = 5.74, df = 1 (P = 0.02); I2 =83%


-2 -1 0 1 2




Analysis 1.6. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 6 Eye drops.



Outcome: 6 Eye drops



Sanchez-Palacios 2001 20 2.4 (2) 20 5 (3) 3.5 % -1.00 [ -1.66, -0.34 ]

Voltolini 2001 15 4.2 (5) 15 7.6 (6.5) 2.9 % -0.57 [ -1.30, 0.16 ]

Cao 2007 29 2.07 (1.46) 37 2.97 (2.17) 6.4 % -0.47 [ -0.96, 0.02 ]

Troise 1995 15 6 (7) 16 8 (6.6) 3.1 % -0.29 [ -1.00, 0.42 ]

de Blay 2007 53 0.35 (0.8) 50 0.54 (0.85) 10.3 % -0.23 [ -0.62, 0.16 ]

Andre 2003 44 0.68 (1.895) 45 1.07 (1.604) 8.9 % -0.22 [ -0.64, 0.20 ]

Dahl 2006a 61 0.79 (1.72) 32 0.92 (1.78) 8.4 % -0.07 [ -0.50, 0.35 ]

Pradalier 1999 62 0.59 (1.221) 61 0.68 (1.594) 12.4 % -0.06 [ -0.42, 0.29 ]

Dubakiene 2003 47 0.131 (0.423) 53 0.15 (0.373) 10.0 % -0.03 [ -0.43, 0.36 ]

Ott 2008 123 0.97 (5.36) 60 0.33 (0.65) 16.2 % 0.14 [ -0.16, 0.45 ]

Moreno-Ancillo 2007 51 0.49 (0.5) 49 0.42 (0.46) 10.0 % 0.14 [ -0.25, 0.54 ]

Khinchi 2004 18 1.99 (2.981) 19 1.57 (2.148) 3.7 % 0.16 [ -0.49, 0.80 ]

Vervloet 2007 22 0.35 (0.68) 21 0.17 (0.55) 4.3 % 0.28 [ -0.32, 0.89 ]

Total (95% CI) 560 478 100.0 % -0.10 [ -0.22, 0.03 ]Heterogeneity: Chi2 = 18.11, df = 12 (P = 0.11); I2 =34%


-2 -1 0 1 2




Analysis 1.7. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 7 Combined symptom-medication scores.



Outcome: 7 Combined symptom-medication scores



Pfaar 2008 42 91.8 (103.6) 48 151.1 (113) 29.9 % -0.54 [ -0.96, -0.12 ]

Bufe 2004 83 0.5 (0.44) 78 0.6 (0.44) 38.1 % -0.23 [ -0.54, 0.08 ]

Moreno-Ancillo 2007 51 0.73 (0.61) 49 0.67 (0.45) 32.0 % 0.11 [ -0.28, 0.50 ]

Total (95% CI) 176 175 100.0 % -0.21 [ -0.55, 0.13 ]Heterogeneity: Tau2 = 0.05; Chi2 = 4.94, df = 2 (P = 0.08); I2 =59%


-4 -2 0 2 4


Analysis 1.8. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 8 Conjunctival immediateallergen sensitivity.



Outcome: 8 Conjunctival immediate allergen sensitivity



Smith 2004 45 34.97 (32.26) 46 33.26 (30.55) 31.7 % 0.05 [ -0.36, 0.47 ]


Horak 1998 21 6.5 (9.16) 20 2.7 (2.38) 19.8 % 0.55 [ -0.07, 1.18 ]

Mortemousque 2003 26 30.861 (27.871) 19 11.65 (10.164) 20.1 % 0.85 [ 0.23, 1.47 ]

Total (95% CI) 130 120 100.0 % 0.35 [ 0.00, 0.69 ]Heterogeneity: Tau2 = 0.05; Chi2 = 5.31, df = 3 (P = 0.15); I2 =43%


-4 -2 0 2 4

Favours Placebo Favours SLIT



Analysis 1.9. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 9 Total ocular symptomscores: Seasonal and perennial.



Outcome: 9 Total ocular symptom scores: Seasonal and perennial



1 Seasonal

Feliziani 1995 18 1.3 (0.3) 16 2.1 (0.5) 1.6 % -1.92 [ -2.75, -1.09 ]

Ariano 2001 10 0.7 (0.48) 10 1.9 (0.82) 1.1 % -1.71 [ -2.77, -0.65 ]

Passalacqua 1999 15 27.2 (12.6) 15 45.3 (16.8) 1.7 % -1.19 [ -1.97, -0.40 ]

Palma-Carlos 2006 17 22.85 (27.02) 16 58.29 (41.21) 1.9 % -1.00 [ -1.73, -0.27 ]

Panzner 2008 20 60.2 (81.25) 15 185.67 (183.85) 2.0 % -0.91 [ -1.62, -0.20 ]

Casanovas 1994 9 1.29 (0.73) 6 2.5 (1.96) 1.0 % -0.85 [ -1.94, 0.24 ]

Troise 1995 15 43 (50) 16 79 (40) 1.9 % -0.78 [ -1.51, -0.04 ]

Khinchi 2004 18 0.87 (0.576) 19 1.32 (0.75) 2.1 % -0.66 [ -1.32, 0.01 ]


Dahl 2006b 282 0.7 (0.6) 286 1.1 (0.8) 5.1 % -0.56 [ -0.73, -0.40 ]

Voltolini 2001 15 34.6 (39) 15 68 (75) 1.9 % -0.54 [ -1.27, 0.19 ]

Wahn 2009 131 0.77 (1.016) 135 1.34 (1.194) 4.6 % -0.51 [ -0.76, -0.27 ]

Dubakiene 2003 47 0.24 (0.27) 53 0.41 (0.39) 3.5 % -0.50 [ -0.90, -0.10 ]

Andre 2003 26 1.11 (0.91) 48 1.69 (1.48) 3.0 % -0.44 [ -0.92, 0.04 ]

Vourdas 1998 33 0.199 (0.466) 31 0.56 (1.259) 3.0 % -0.38 [ -0.88, 0.11 ]

Didier 2007 136 0.95 (1.1) 148 1.4 (1.24) 4.7 % -0.38 [ -0.62, -0.15 ]

Pradalier 1999 62 1.06 (1.02) 61 1.55 (1.53) 3.8 % -0.38 [ -0.73, -0.02 ]

de Blay 2007 53 7.79 (9.28) 51 11.18 (10.82) 3.6 % -0.33 [ -0.72, 0.05 ]

Valovirta 2006 32 0.8 (1.2) 33 1.1 (0.9) 3.0 % -0.28 [ -0.77, 0.21 ]

Horak 1998 21 2 (3.46) 20 2.9 (4.12) 2.3 % -0.23 [ -0.85, 0.38 ]

Bowen 2004 27 1.96 (1.9) 29 2.38 (1.92) 2.8 % -0.22 [ -0.74, 0.31 ]

La Rosa 1999 16 0.23 (0.445) 17 0.35 (0.629) 2.1 % -0.21 [ -0.90, 0.47 ]

Bufe 2008 117 0.66 (0.76) 121 0.79 (0.73) 4.6 % -0.17 [ -0.43, 0.08 ]

Dahl 2006a 61 0.75 (0.78) 32 0.88 (0.68) 3.4 % -0.17 [ -0.60, 0.26 ]

-4 -2 0 2 4


(Continued . . . )





Ott 2008 123 1.28 (1.77) 60 1.51 (1.93) 4.2 % -0.13 [ -0.43, 0.18 ]

Durham 2006 141 0.74 (0.78) 136 0.81 (0.75) 4.7 % -0.09 [ -0.33, 0.14 ]

Vervloet 2007 22 1.14 (1.14) 21 1.24 (1.4) 2.4 % -0.08 [ -0.68, 0.52 ]

Moreno-Ancillo 2007 51 0.48 (0.39) 49 0.46 (0.31) 3.6 % 0.06 [ -0.34, 0.45 ]


Smith 2004 45 1.09 (1.224) 51 0.86 (0.748) 3.5 % 0.23 [ -0.18, 0.63 ]

Subtotal (95% CI) 1616 1564 88.2 % -0.38 [ -0.50, -0.25 ]Heterogeneity: Tau2 = 0.06; Chi2 = 69.34, df = 29 (P = 0.00004); I2 =58%


2 Perennial

Passalacqua 1998 10 12.7 (4.6) 10 28 (11.1) 1.1 % -1.72 [ -2.78, -0.66 ]

Mortemousque 2003 26 5.76 (0.9) 19 7 (1.33) 2.2 % -1.11 [ -1.75, -0.47 ]

Cao 2007 29 1.66 (1.03) 37 2.43 (1.39) 2.9 % -0.61 [ -1.11, -0.11 ]


Hirsch 1997 15 0.36 (0.69) 15 0.31 (0.62) 1.9 % 0.07 [ -0.64, 0.79 ]

Aydogan 2007 9 0.22 (0.43) 9 0.01 (0.02) 1.3 % 0.66 [ -0.30, 1.61 ]

Subtotal (95% CI) 109 110 11.8 % -0.52 [ -1.05, 0.01 ]Heterogeneity: Tau2 = 0.30; Chi2 = 16.82, df = 5 (P = 0.005); I2 =70%




-4 -2 0 2 4




Analysis 1.10. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 10 Total ocular symptomscores: Adults and children.



Outcome: 10 Total ocular symptom scores: Adults and children



1 Children

Cao 2007 29 1.66 (1.03) 37 2.43 (1.39) 2.9 % -0.61 [ -1.11, -0.11 ]

Wahn 2009 131 0.77 (1.016) 135 1.34 (1.194) 4.7 % -0.51 [ -0.76, -0.27 ]

Vourdas 1998 33 0.199 (0.466) 31 0.56 (1.259) 2.9 % -0.38 [ -0.88, 0.11 ]

Bufe 2008 117 0.91 (0.95) 121 1.23 (1.14) 4.6 % -0.30 [ -0.56, -0.05 ]

Valovirta 2006 32 0.8 (1.2) 33 1.1 (0.9) 3.0 % -0.28 [ -0.77, 0.21 ]

La Rosa 1999 16 0.66 (0.76) 17 0.79 (0.73) 2.0 % -0.17 [ -0.85, 0.51 ]

Hirsch 1997 15 0.36 (0.69) 15 0.31 (0.62) 1.9 % 0.07 [ -0.64, 0.79 ]


Aydogan 2007 9 0.22 (0.43) 9 0.01 (0.02) 1.3 % 0.66 [ -0.30, 1.61 ]



2 Adults

Feliziani 1995 18 1.3 (0.3) 16 2.1 (0.5) 1.6 % -1.92 [ -2.75, -1.09 ]

Passalacqua 1998 10 12.7 (4.6) 10 28 (11.1) 1.1 % -1.72 [ -2.78, -0.66 ]

Ariano 2001 10 0.7 (0.48) 10 1.9 (0.82) 1.1 % -1.71 [ -2.77, -0.65 ]

Passalacqua 1999 15 27.2 (12.6) 15 45.3 (16.8) 1.7 % -1.19 [ -1.97, -0.40 ]

Mortemousque 2003 26 5.76 (0.9) 19 7 (1.33) 2.2 % -1.11 [ -1.75, -0.47 ]

Palma-Carlos 2006 17 22.85 (27.02) 16 58.29 (41.21) 1.9 % -1.00 [ -1.73, -0.27 ]

Panzner 2008 20 60.2 (81.25) 15 185.67 (183.85) 2.0 % -0.91 [ -1.62, -0.20 ]

Casanovas 1994 9 1.29 (0.73) 6 2.5 (1.96) 1.0 % -0.85 [ -1.94, 0.24 ]

Troise 1995 15 43 (50) 16 79 (40) 1.9 % -0.78 [ -1.51, -0.04 ]

Khinchi 2004 18 0.87 (0.576) 19 1.32 (0.75) 2.1 % -0.66 [ -1.32, 0.01 ]


Dahl 2006b 282 0.7 (0.6) 286 1.1 (0.8) 5.2 % -0.56 [ -0.73, -0.40 ]

-4 -2 0 2 4


(Continued . . . )





Voltolini 2001 15 34.6 (39) 15 68 (75) 1.9 % -0.54 [ -1.27, 0.19 ]

Dubakiene 2003 47 0.24 (0.27) 53 0.41 (0.39) 3.6 % -0.50 [ -0.90, -0.10 ]


Andre 2003 26 1.11 (0.91) 48 1.69 (1.48) 3.0 % -0.44 [ -0.92, 0.04 ]

Didier 2007 136 0.95 (1.1) 148 1.4 (1.24) 4.7 % -0.38 [ -0.62, -0.15 ]

Pradalier 1999 62 1.06 (1.02) 61 1.55 (1.53) 3.9 % -0.38 [ -0.73, -0.02 ]

de Blay 2007 53 7.79 (9.28) 51 11.18 (10.82) 3.6 % -0.33 [ -0.72, 0.05 ]

Horak 1998 21 2 (3.46) 20 2.9 (4.12) 2.3 % -0.23 [ -0.85, 0.38 ]

Bowen 2004 27 1.96 (1.9) 29 2.38 (1.92) 2.8 % -0.22 [ -0.74, 0.31 ]

Dahl 2006a 61 0.75 (0.78) 32 0.88 (0.68) 3.4 % -0.17 [ -0.60, 0.26 ]

Ott 2008 123 1.28 (1.77) 60 1.51 (1.93) 4.2 % -0.13 [ -0.43, 0.18 ]

Durham 2006 141 0.74 (0.78) 136 0.81 (0.75) 4.7 % -0.09 [ -0.33, 0.14 ]

Vervloet 2007 22 1.14 (1.14) 21 1.24 (1.4) 2.4 % -0.08 [ -0.68, 0.52 ]

Moreno-Ancillo 2007 51 0.48 (0.39) 49 0.46 (0.31) 3.6 % 0.06 [ -0.34, 0.45 ]

Smith 2004 45 1.09 (1.224) 51 0.86 (0.748) 3.5 % 0.23 [ -0.18, 0.63 ]

Subtotal (95% CI) 1304 1238 73.4 % -0.48 [ -0.63, -0.32 ]Heterogeneity: Tau2 = 0.08; Chi2 = 71.73, df = 26 (P<0.00001); I2 =64%




-4 -2 0 2 4




Analysis 1.11. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 11 Total ocular symptomscores: Publication year.



Outcome: 11 Total ocular symptom scores: Publication year



1 1994 - 1999

Feliziani 1995 18 1.3 (0.3) 16 2.1 (0.5) 1.6 % -1.92 [ -2.75, -1.09 ]

Passalacqua 1998 10 12.7 (4.6) 10 28 (11.1) 1.1 % -1.72 [ -2.78, -0.66 ]

Passalacqua 1999 15 27.2 (12.6) 15 45.3 (16.8) 1.7 % -1.19 [ -1.97, -0.40 ]

Casanovas 1994 9 1.29 (0.73) 6 2.5 (1.96) 1.0 % -0.85 [ -1.94, 0.24 ]

Troise 1995 15 43 (50) 16 79 (40) 1.9 % -0.78 [ -1.51, -0.04 ]


Vourdas 1998 33 0.199 (0.466) 31 0.56 (1.259) 3.0 % -0.38 [ -0.88, 0.11 ]

Pradalier 1999 62 1.06 (1.02) 61 1.55 (1.53) 3.8 % -0.38 [ -0.73, -0.02 ]

Horak 1998 21 2 (3.46) 20 2.9 (4.12) 2.3 % -0.23 [ -0.85, 0.38 ]

La Rosa 1999 16 0.23 (0.445) 17 0.35 (0.629) 2.1 % -0.21 [ -0.90, 0.47 ]

Hirsch 1997 15 0.36 (0.69) 15 0.31 (0.62) 1.9 % 0.07 [ -0.64, 0.79 ]



2 2000 - 2005

Ariano 2001 10 0.7 (0.48) 10 1.9 (0.82) 1.1 % -1.71 [ -2.77, -0.65 ]

Mortemousque 2003 26 5.76 (0.9) 19 7 (1.33) 2.2 % -1.11 [ -1.75, -0.47 ]

Khinchi 2004 18 0.87 (0.576) 19 1.32 (0.75) 2.1 % -0.66 [ -1.32, 0.01 ]

Voltolini 2001 15 34.6 (39) 15 68 (75) 1.9 % -0.54 [ -1.27, 0.19 ]

Dubakiene 2003 47 0.24 (0.27) 53 0.41 (0.39) 3.5 % -0.50 [ -0.90, -0.10 ]


Andre 2003 26 1.11 (0.91) 48 1.69 (1.48) 3.0 % -0.44 [ -0.92, 0.04 ]

Bowen 2004 27 1.96 (1.9) 29 2.38 (1.92) 2.8 % -0.22 [ -0.74, 0.31 ]


Smith 2004 45 1.09 (1.224) 51 0.86 (0.748) 3.5 % 0.23 [ -0.18, 0.63 ]

-4 -2 0 2 4


(Continued . . . )







3 2006 - 2009

Palma-Carlos 2006 17 22.85 (27.02) 16 58.29 (41.21) 1.9 % -1.00 [ -1.73, -0.27 ]

Panzner 2008 20 60.2 (81.25) 15 185.67 (183.85) 2.0 % -0.91 [ -1.62, -0.20 ]

Cao 2007 29 1.66 (1.03) 37 2.43 (1.39) 2.9 % -0.61 [ -1.11, -0.11 ]

Dahl 2006b 282 0.7 (0.6) 286 1.1 (0.8) 5.1 % -0.56 [ -0.73, -0.40 ]

Wahn 2009 131 0.77 (1.016) 135 1.34 (1.194) 4.6 % -0.51 [ -0.76, -0.27 ]

Didier 2007 136 0.95 (1.1) 148 1.4 (1.24) 4.7 % -0.38 [ -0.62, -0.15 ]

de Blay 2007 53 7.79 (9.28) 51 11.18 (10.82) 3.6 % -0.33 [ -0.72, 0.05 ]

Valovirta 2006 32 0.8 (1.2) 33 1.1 (0.9) 3.0 % -0.28 [ -0.77, 0.21 ]

Bufe 2008 117 0.66 (0.76) 121 0.79 (0.73) 4.6 % -0.17 [ -0.43, 0.08 ]

Dahl 2006a 61 0.75 (0.78) 32 0.88 (0.68) 3.4 % -0.17 [ -0.60, 0.26 ]

Ott 2008 123 1.28 (1.77) 60 1.51 (1.93) 4.2 % -0.13 [ -0.43, 0.18 ]

Durham 2006 141 0.74 (0.78) 136 0.81 (0.75) 4.7 % -0.09 [ -0.33, 0.14 ]

Vervloet 2007 22 1.14 (1.14) 21 1.24 (1.4) 2.4 % -0.08 [ -0.68, 0.52 ]

Moreno-Ancillo 2007 51 0.48 (0.39) 49 0.46 (0.31) 3.6 % 0.06 [ -0.34, 0.45 ]

Aydogan 2007 9 0.22 (0.43) 9 0.01 (0.02) 1.3 % 0.66 [ -0.30, 1.61 ]





-4 -2 0 2 4




Analysis 1.12. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 12 Total ocular symptomscores: Treatment > 12 months.



Outcome: 12 Total ocular symptom scores: Treatment > 12 months



1 12 months or less

Feliziani 1995 18 1.3 (0.3) 16 2.1 (0.5) 1.6 % -1.92 [ -2.75, -1.09 ]

Ariano 2001 10 0.7 (0.48) 10 1.9 (0.82) 1.1 % -1.71 [ -2.77, -0.65 ]

Passalacqua 1999 15 27.2 (12.6) 15 45.3 (16.8) 1.7 % -1.19 [ -1.97, -0.40 ]

Panzner 2008 20 60.2 (81.25) 15 185.67 (183.85) 2.0 % -0.91 [ -1.62, -0.20 ]

Casanovas 1994 9 1.29 (0.73) 6 2.5 (1.96) 1.0 % -0.85 [ -1.94, 0.24 ]

Troise 1995 15 43 (50) 16 79 (40) 1.9 % -0.78 [ -1.51, -0.04 ]

Cao 2007 29 1.66 (1.03) 37 2.43 (1.39) 2.9 % -0.61 [ -1.11, -0.11 ]


Dahl 2006b 282 0.7 (0.6) 286 1.1 (0.8) 5.1 % -0.56 [ -0.73, -0.40 ]

Voltolini 2001 15 34.6 (39) 15 68 (75) 1.9 % -0.54 [ -1.27, 0.19 ]

Wahn 2009 131 0.77 (1.016) 135 1.34 (1.194) 4.6 % -0.51 [ -0.76, -0.27 ]

Dubakiene 2003 47 0.24 (0.27) 53 0.41 (0.39) 3.5 % -0.50 [ -0.90, -0.10 ]


Andre 2003 26 1.11 (0.91) 48 1.69 (1.48) 3.0 % -0.44 [ -0.92, 0.04 ]

Didier 2007 136 0.95 (1.1) 148 1.4 (1.24) 4.7 % -0.38 [ -0.62, -0.15 ]

Pradalier 1999 62 1.06 (1.02) 61 1.55 (1.53) 3.8 % -0.38 [ -0.73, -0.02 ]

de Blay 2007 53 7.79 (9.28) 51 11.18 (10.82) 3.6 % -0.33 [ -0.72, 0.05 ]

Bowen 2004 27 1.96 (1.9) 29 2.38 (1.92) 2.8 % -0.22 [ -0.74, 0.31 ]

Bufe 2008 117 0.66 (0.76) 121 0.79 (0.73) 4.6 % -0.17 [ -0.43, 0.08 ]

Dahl 2006a 61 0.75 (0.78) 32 0.88 (0.68) 3.4 % -0.17 [ -0.60, 0.26 ]

Ott 2008 123 1.28 (1.77) 60 1.51 (1.93) 4.2 % -0.13 [ -0.43, 0.18 ]

Durham 2006 141 0.74 (0.78) 136 0.81 (0.75) 4.7 % -0.09 [ -0.33, 0.14 ]

Vervloet 2007 22 1.14 (1.14) 21 1.24 (1.4) 2.4 % -0.08 [ -0.68, 0.52 ]

Moreno-Ancillo 2007 51 0.48 (0.39) 49 0.46 (0.31) 3.6 % 0.06 [ -0.34, 0.45 ]

-4 -2 0 2 4


(Continued . . . )





Hirsch 1997 15 0.36 (0.69) 15 0.31 (0.62) 1.9 % 0.07 [ -0.64, 0.79 ]

Aydogan 2007 9 0.22 (0.43) 9 0.01 (0.02) 1.3 % 0.66 [ -0.30, 1.61 ]



2 13 months or more

Passalacqua 1998 10 12.7 (4.6) 10 28 (11.1) 1.1 % -1.72 [ -2.78, -0.66 ]

Mortemousque 2003 26 5.76 (0.9) 19 7 (1.33) 2.2 % -1.11 [ -1.75, -0.47 ]

Palma-Carlos 2006 17 22.85 (27.02) 16 58.29 (41.21) 1.9 % -1.00 [ -1.73, -0.27 ]

Khinchi 2004 18 0.87 (0.576) 19 1.32 (0.75) 2.1 % -0.66 [ -1.32, 0.01 ]

Vourdas 1998 33 0.199 (0.466) 31 0.56 (1.259) 3.0 % -0.38 [ -0.88, 0.11 ]

Valovirta 2006 32 0.8 (1.2) 33 1.1 (0.9) 3.0 % -0.28 [ -0.77, 0.21 ]

Horak 1998 21 2 (3.46) 20 2.9 (4.12) 2.3 % -0.23 [ -0.85, 0.38 ]

La Rosa 1999 16 0.23 (0.445) 17 0.35 (0.629) 2.1 % -0.21 [ -0.90, 0.47 ]


Smith 2004 45 1.09 (1.224) 51 0.86 (0.748) 3.5 % 0.23 [ -0.18, 0.63 ]





-4 -2 0 2 4




Analysis 1.13. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 13 Total ocular symptomscores: Fixed-effects model.



Outcome: 13 Total ocular symptom scores: Fixed-effects model



Feliziani 1995 18 1.3 (0.3) 16 2.1 (0.5) 0.7 % -1.92 [ -2.75, -1.09 ]

Passalacqua 1998 10 12.7 (4.6) 10 28 (11.1) 0.4 % -1.72 [ -2.78, -0.66 ]

Ariano 2001 10 0.7 (0.48) 10 1.9 (0.82) 0.4 % -1.71 [ -2.77, -0.65 ]

Passalacqua 1999 15 27.2 (12.6) 15 45.3 (16.8) 0.8 % -1.19 [ -1.97, -0.40 ]

Mortemousque 2003 26 5.76 (0.9) 19 7 (1.33) 1.2 % -1.11 [ -1.75, -0.47 ]

Palma-Carlos 2006 17 22.85 (27.02) 16 58.29 (41.21) 0.9 % -1.00 [ -1.73, -0.27 ]

Panzner 2008 20 60.2 (81.25) 15 185.67 (183.85) 0.9 % -0.91 [ -1.62, -0.20 ]

Casanovas 1994 9 1.29 (0.73) 6 2.5 (1.96) 0.4 % -0.85 [ -1.94, 0.24 ]

Troise 1995 15 43 (50) 16 79 (40) 0.9 % -0.78 [ -1.51, -0.04 ]

Khinchi 2004 18 0.87 (0.576) 19 1.32 (0.75) 1.1 % -0.66 [ -1.32, 0.01 ]

Cao 2007 29 1.66 (1.03) 37 2.43 (1.39) 1.9 % -0.61 [ -1.11, -0.11 ]


Dahl 2006b 282 0.7 (0.6) 286 1.1 (0.8) 16.8 % -0.56 [ -0.73, -0.40 ]

Voltolini 2001 15 34.6 (39) 15 68 (75) 0.9 % -0.54 [ -1.27, 0.19 ]

Wahn 2009 131 0.77 (1.016) 135 1.34 (1.194) 7.9 % -0.51 [ -0.76, -0.27 ]

Dubakiene 2003 47 0.24 (0.27) 53 0.41 (0.39) 3.0 % -0.50 [ -0.90, -0.10 ]


Andre 2003 26 1.11 (0.91) 48 1.69 (1.48) 2.0 % -0.44 [ -0.92, 0.04 ]

Vourdas 1998 33 0.199 (0.466) 31 0.56 (1.259) 1.9 % -0.38 [ -0.88, 0.11 ]

Didier 2007 136 0.95 (1.1) 148 1.4 (1.24) 8.6 % -0.38 [ -0.62, -0.15 ]

Pradalier 1999 62 1.06 (1.02) 61 1.55 (1.53) 3.7 % -0.38 [ -0.73, -0.02 ]

de Blay 2007 53 7.79 (9.28) 51 11.18 (10.82) 3.2 % -0.33 [ -0.72, 0.05 ]

Valovirta 2006 32 0.8 (1.2) 33 1.1 (0.9) 2.0 % -0.28 [ -0.77, 0.21 ]

Horak 1998 21 2 (3.46) 20 2.9 (4.12) 1.3 % -0.23 [ -0.85, 0.38 ]

Bowen 2004 27 1.96 (1.9) 29 2.38 (1.92) 1.7 % -0.22 [ -0.74, 0.31 ]

-4 -2 0 2 4


(Continued . . . )





La Rosa 1999 16 0.23 (0.445) 17 0.35 (0.629) 1.0 % -0.21 [ -0.90, 0.47 ]

Bufe 2008 117 0.66 (0.76) 121 0.79 (0.73) 7.3 % -0.17 [ -0.43, 0.08 ]

Dahl 2006a 61 0.75 (0.78) 32 0.88 (0.68) 2.6 % -0.17 [ -0.60, 0.26 ]

Ott 2008 123 1.28 (1.77) 60 1.51 (1.93) 5.0 % -0.13 [ -0.43, 0.18 ]

Durham 2006 141 0.74 (0.78) 136 0.81 (0.75) 8.5 % -0.09 [ -0.33, 0.14 ]

Vervloet 2007 22 1.14 (1.14) 21 1.24 (1.4) 1.3 % -0.08 [ -0.68, 0.52 ]

Moreno-Ancillo 2007 51 0.48 (0.39) 49 0.46 (0.31) 3.1 % 0.06 [ -0.34, 0.45 ]

Hirsch 1997 15 0.36 (0.69) 15 0.31 (0.62) 0.9 % 0.07 [ -0.64, 0.79 ]


Smith 2004 45 1.09 (1.224) 51 0.86 (0.748) 2.9 % 0.23 [ -0.18, 0.63 ]

Aydogan 2007 9 0.22 (0.43) 9 0.01 (0.02) 0.5 % 0.66 [ -0.30, 1.61 ]

Total (95% CI) 1725 1674 100.0 % -0.37 [ -0.43, -0.30 ]Heterogeneity: Chi2 = 87.82, df = 35 (P<0.00001); I2 =60%


-4 -2 0 2 4


A P P E N D I C E S

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Conjunctivitis, Allergic#2 conjunctivitis#3 MeSH descriptor Rhinitis, Allergic, Seasonal#4 MeSH descriptor Rhinitis, Allergic, Perennial#5 rhiniti*#6 pollen near/3 allerg*#7 hayfever#8 hay near/2 fever#9 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8)#10 MeSH descriptor Immunotherapy#11 immunotherap*#12 MeSH descriptor Desensitization, Immunologic#13 desensiti*#14 MeSH descriptor Allergens#15 allergen*#16 (#10 OR #11 OR #12 OR #13 OR #14 OR #15)#17 MeSH descriptor Administration, Sublingual



#18 sublingual*#19 SLIT#20 (#17 OR #18 OR #19)#21 (#9 AND #16 AND #20)

Appendix 2. MEDLINE search strategy

1 randomized controlled trial.pt.2 (randomized or randomised).ab,ti.3 placebo.ab,ti.4 dt.fs.5 randomly.ab,ti.6 trial.ab,ti.7 groups.ab,ti.8 or/1-79 exp animals/10 exp humans/11 9 not (9 and 10)12 8 not 1113 exp conjunctivitis, allergic/14 conjunctivitis.tw.15 exp rhinitis, allergic, seasonal/16 exp rhinitis, allergic, perennial/17 rhiniti$.tw.18 (pollen adj3 allerg$).tw.19 hayfever.tw.20 (hay adj2 fever).tw.21 or/13-2022 exp immunotherapy/23 immunotherap$.tw.24 exp desensitization, immunologic/25 desensiti$.tw.26 exp allergens/27 allergen$.tw.28 or/22-2729 exp administration, sublingual/30 sublingual$.tw.31 SLIT.tw.32 or/29-3133 21 and 28 and 3234 12 and 33The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville et al (Glanville 2006).

Appendix 3. EMBASE search strategy

1 exp randomized controlled trial/2 exp randomization/3 exp double blind procedure/4 exp single blind procedure/5 random$.tw.6 or/1-57 (animal or animal experiment).sh.8 human.sh.



9 7 and 810 7 not 911 6 not 1012 exp clinical trial/13 (clin$ adj3 trial$).tw.14 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.15 exp placebo/16 placebo$.tw.17 random$.tw.18 exp experimental design/19 exp crossover procedure/20 exp control group/21 exp latin square design/22 or/12-2123 22 not 1024 23 not 1125 exp comparative study/26 exp evaluation/27 exp prospective study/28 (control$ or prospectiv$ or volunteer$).tw.29 or/25-2830 29 not 1031 30 not (11 or 23)32 11 or 24 or 3133 exp allergic conjunctivitis/34 conjunctivitis.tw.35 exp rhinitis/36 exp allergic rhinitis/37 rhiniti$.tw.38 (pollen adj3 allerg$).tw.39 hayfever.tw.40 (hay adj2 fever).tw.41 or/33-4042 exp immunotherapy/43 immunotherap$.tw.44 exp desensitization/45 desensiti$.tw.46 exp allergen/47 allergen$.tw.48 or/42-4749 exp sublingual drug administration/50 sublingual$.tw.51 SLIT.tw.52 41 and 48 and 5153 32 and 52



Appendix 4. LILACS search strategy

conjunctivitis or rhinitis or pollen or hayfever and immunotherap$ or desensiti$ or allergen$ and sublingual$

Appendix 5. Web of Science search strategy

Topic=(clinical trial* OR research design OR comparative stud* OR evaluation stud* OR controlled trial* OR follow-up stud* ORprospective stud* OR random* OR placebo* OR single blind* OR double blind*)Topic=(conjunctivitis or rhinitis or pollen or hayfever) AND Topic=(immunotherap* or desensiti* or allergen*) AND Topic=(sublin-gual*)Timespan=All Years.

Appendix 6. BIOSIS Previews search strategy

Topic=(conjunctivitis or rhinitis or pollen or hayfever) AND Topic=(immunotherap* or desensiti* or allergen*) AND Topic=(sublin-gual*)Timespan=All Years

Appendix 7. metaRegister of Controlled Trials search strategy

conjunctivitis and sublingual

Appendix 8. ClinicalTrials.gov search strategy

Conjunctivitis AND Sublingual

Appendix 9. Australian New Zealand Clinical Trials Registry search strategy

sublingual AND immunotherapySLIT AND allergen AND immunotherapy

Appendix 10. UK Clinical Trials Gateway search strategy

(immunotherapy or desensiti*) and conjunctivitis

Appendix 11. Scopus search strategy

conjunctivi* AND immunotherap* AND sublingual*

H I S T O R Y

Protocol first published: Issue 2, 2009

Review first published: Issue 7, 2011



C O N T R I B U T I O N S O F A U T H O R S

Conceiving the review: SRD, GWC

Designing the review: MC, MP

Co-ordinating the review: MC, MP

Data collection for the review

- Designing electronic search strategies: Cochrane Eyes and Vision Group

- Undertaking manual searches: MC, MP

- Screening search results: AS, MC, MP

- Organising retrieval of papers: MC, MP

- Screening retrieved papers against inclusion criteria: AS, MC, MP

- Appraising quality of papers: MC, MP

- Extracting data from papers: MC, MP

- Writing to authors of papers for additional information: MC, MP

- Providing additional data about papers: MC, MP

- Obtaining and screening data on unpublished studies: MC, MP

Data management for the review

- Entering data into RevMan: MC, MP

- RevMan statistical data: MP, MC, AS

- Other statistical analysis not using RevMan: MP, MC, AS

- Double entry of data (not in RevMan): (data entered by person one; data entered by person two:) MC, AS

Analysis of data: AG, JT

Interpretation of data

- Providing a methodological perspective: MC, MP, AS, AG

- Providing a clinical perspective: SRD, GWC, MC, MP

- Providing a policy perspective: SRD, GWC, MC

- Providing a consumer perspective: SRD, GWC, MC

Writing the review: MC, MP, AS, SRD, GWC

Providing general advice on the review: SRD

Securing funding for the review: SRD

Performing previous work that was the foundation of the current study: SRD, GWC, MC, MP

Reading and checking review before submission: SRD, GWC, AS



D E C L A R A T I O N S O F I N T E R E S T

The Department of Upper Respiratory Medicine, National Heart & Lung Institute, London, UK, headed by Professor Durham, hasreceived financial support from ALK-Abelló, Horsholm, Denmark - manufacturers of allergen extracts. Professor Durham

• has received lecture fees, ad hoc consultancy payments and research funding from ALK-Abelló, via Imperial College.

• has received consultancy fees from Circassia UK, a manufacturer of allergen peptide vaccines.

• is principle investigator on immunotherapy trials of allergen vaccines from ALK-Abelló.

Professor Canonica’s department at the University of Genoa, Italy has received research grants from Alk-Abelló, Lofarma and Stallergènes- manufacturers of allergen extracts.

Professor Sheikh has received honoraria and consultancy fees from ALK-Abelló.

S O U R C E S O F S U P P O R T

Internal sources

• Imperial College of London and National Heart and Lung Institute, UK.Researcher’s salary

• University of Genoa, Italy.Researcher’s salary

External sources

• No sources of support supplied

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

A summary of findings table (SoF) was developed and the quality of the evidence was graded using the GRADE approach.



sub lingual immunotherapy cochrane sys rev july 2011 fulltext

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