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 Library 2011, Issue 7 http://www.thecochranelibrary.com
Sublingual immunotherapy for treating allergic conjunctivitis (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 1 Total ocular symptom scores. . Analysis 1.2. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 2 Itchy/Gritty eyes. . . . . . Analysis 1.3. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 3 Watery eyes. . . . . . . . Analysis 1.4. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 4 Red eyes. . . . . . . . . Analysis 1.5. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 5 Swollen eyes. . . . . . . . Analysis 1.6. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 6 Eye drops. . . . . . . . . Analysis 1.7. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 7 Combined symptom-medication scores. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.8. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 8 Conjunctival immediate allergen sensitivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.9. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 9 Total ocular symptom scores: Seasonal and perennial. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.10. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 10 Total ocular symptom scores: Adults and children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.11. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 11 Total ocular symptom scores: Publication year. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.12. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 12 Total ocular symptom scores: Treatment > 12 months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.13. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 13 Total ocular symptom scores: Fixedeffects model. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 6 6 6 8 9 13 14 16 17 20 20 21 28 86 87 89 90 91 92 93 94 94 95 97 99 101 103 104 107 107 108 109 109
[Intervention Review]
Sublingual immunotherapy for treating allergic conjunctivitis

Moises A Calderon1 , Martin Penagos1 , Aziz Sheikh2 , Giorgio W Canonica3 , Stephen Durham1
1 Department of Allergy and Respiratory Medicine, Royal Brompton Hospital, London, UK. 2 Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK. 3 Allergy and Respiratory Diseases Clinic, Department of Internal Medicine (DIMI), University of Genoa, Genoa, Italy
Contact address: Moises A Calderon, Department of Allergy and Respiratory Medicine, Royal Brompton Hospital, Imperial College School of Medicine at the National Heart and Lung Institute, London, SW3 6LY, UK. m.calderon@imperial.ac.uk. 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 conjunctivitis. Cochrane Database of Systematic Reviews 2011, Issue 7. Art. No.: CD007685. DOI: 10.1002/14651858.CD007685.pub2. Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT 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 ocular allergy have not been well established. Objectives To evaluate the efcacy of SLIT compared with placebo for reductions in ocular symptoms, topical ocular medication requirements and 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 on Health Sciences (LILACS) (January 1982 to January 2011), Web of Science (January 1970 to January 2011), Biosis Previews, (January 1979 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 the search for trials. All electronic databases except for SCOPUS, the UK Clinical Trials Gateway and ANZCTR were last searched on 19 January 2011. Selection criteria Randomised controlled trials (RCTs), double-masked and placebo controlled, which evaluated the efcacy of SLIT in patients with symptoms 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 as itchy 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.
Sublingual immunotherapy for treating allergic conjunctivitis (Review) Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1
Main results Forty-two trials (n = 3958 total participants; n= 2011 SLIT and n = 1947 placebo) had available data to evaluate the efcacy of SLIT on 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 signicant reduction in both total ocular symptom scores (SMD -0.41; 95% condence 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 the threshold dose for the conjunctival allergen provocation test (SMD 0.35; 95% CI 0.00 to 0.69; P = 0.05; I2 = 43%). No signicant reduction 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 allocation concealment in some studies, statistical heterogeneity and the possibility of publication bias. There is a need for further large rigorously designed studies that study long-term effectiveness after discontinuation of treatment and establish the cost-effectiveness of SLIT.
PLAIN LANGUAGE SUMMARY Sublingual immunotherapy (tablets, spray or drops under the tongue) to treat inammation of the conjunctiva due to allergy Conjunctivitis means inammation of the conjunctiva. The conjunctiva is the thin skin that covers the white part of the eyes and the inside of the eyelids. Allergic conjunctivitis is the inammation of the conjunctiva due to allergy. The most common cause is an allergy to 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 not provide enough relief another option is immunotherapy, which builds immunity to the allergen causing the reaction. Immunotherapy can be given under the tongue, nasally or by injection. This review included 42 trials with a total of 3958 participants with allergic conjunctivitis; 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 conjunctivitis Settings: clinical allergy units Intervention: sublingual immunotherapy Outcomes Illustrative comparative risks* (95% CI) Relative effect (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments
Assumed risk Control
Corresponding risk Sublingual immunotherapy The mean total ocular symptom scores in the intervention groups was 0.41 standard deviations lower (0.53 to 0.28 lower) The mean itchy/gritty eyes in the intervention groups was 0.31 standard deviations lower (0.42 to 0.2 lower) The mean Watery eyes in the intervention groups was 0.23 standard deviations lower (0.34 to 0.11 lower) 3399 (36 studies) moderate1,2 SMD -0.41 (-0.53 to 0.28)
Total ocular symptom The mean total ocular scores symptom scores ranged Symptom scores across control groups from 0.01 to 268 points
Itchy/Gritty eyes Symptom scores
The mean itchy/gritty eyes ranged across control groups from 0.004 to 121 points
3020 (28 studies)
moderate3
SMD -0.31 (-0.42 to -0.2)
Watery eyes Symptom scores
The mean watery eyes ranged across control groups from 0.023 to 44.13 points
2641 (21 studies)
moderate4
SMD -0.23 (-0.34 to 0.11)
Red eyes Symptom scores
The mean red eyes ranged across control groups from 0.02 to 147 points
The mean red eyes in the intervention groups was 0.33 standard deviations lower (0.45 to 0.22 lower)
1211 (20 studies)
moderate5
SMD -0.33 (-0.45 to 0.22)
Eye drops Symptom scores
The mean eye drops The mean eye drops in the ranged across control intervention groups was groups from 0.1 standard deviations 0.17 to 8 points lower (0.22 lower to 0.03 higher) The mean combined symptom-medication scores in the intervention groups was 0.21 standard deviations lower (0.55 lower to 0.13 higher) The mean conjunctival immediate allergen sensitivity in the intervention groups was 0.35 standard deviations higher (0 to 0.69 higher)
1038 (13 studies)
moderate6
SMD -0.1 (-0.22 to 0.03)
Combined symptom- The mean commedication scores bined symptom-medication scores ranged across Symptom scores control groups from 0.6 to 151.1 points
351 (3 studies)
moderate7
SMD -0.21 (-0.55 to 0.13)
Conjunctival immediate The mean conjunctival allergen sensitivity immediate allergen sensiSymptom scores tivity ranged across control groups from 2.7 to 33.26 points
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 the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval;
GRADE Working Group grades of evidence High 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. All the included studies are double-masked and placebo controlled RCTs. Due to the nature of the disease, the majority of the studies aimed to treat rhinoconjunctivitis not the ocular component by itself; only one study was specifically designed to evaluate just conjunctivitis. 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 studies 4,6 Publication bias is likely for this outcome 9 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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BACKGROUND
dendritic cells mature and migrate to proximal draining lymph nodes (for example submaxillary, supercial cervical and internal jugular) as a consequence of changes in expression of surface receptors (Moingeon 2006). Those lymph nodes represent specialised micro-environments favouring the induction of mucosal tolerance through the production of blocking IgG antibodies (IgG2b in mice) and the induction of T lymphocytes with suppressive function (Moingeon 2006). Large-scale trials have conrmed the induction of allergen-specic IgG antibodies after several weeks of therapy, probably SLIT dose-dependent (Dahl 2007; Scadding 2009; Torres-Lima 2002). There is no early suppression of allergen-specic IgE antibodies and a transient early increase in specic IgE antibodies is observed. Current models of subcutaneous immunotherapy propose the induction of antigen-specic regulatory T cells (Scadding 2009). A study showed that SLIT induces regulatory T cell suppression through IL-10 during the early phase and specic non-reactivity and immune deviation of allergen-specic T cells during the later phase of therapy (Bohle 2007).
Description of the condition

Allergic inammation involving the eye is common and may be the most prominent or, in some cases, the only feature of allergy (Bielory 2008a). The prevalence of ocular allergies in the general population 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 least one day of ocular symptoms per week (Berger 2005; Canonica 2007; Torkildsen 2009). Seasonal allergic conjunctivitis (SAC) is due to the direct exposure of the ocular mucosal surfaces to environmental allergens, such as pollens from trees, grasses and weeds, which interact with the pollen-specic immunoglobulin E (IgE) found on the mast cells of the eye (Bielory 2002). Perennial allergic conjunctivitis (PAC) also exhibits an IgE mast cell-mediated hypersensitivity to airborne allergens, more frequently perennial household allergens such as dust mites, moulds and animal dander. Common conjunctival symptoms are itching, tearing, redness and sometimes burning. Both eyes are typically affected simultaneously and, quite often, a family history of hay fever or atopy is elicited (Bielory 2007b; Bielory 2008a). Visual impairment is uncommon, with blurring of vision being the most common corneal symptom (Bielory 2007a).
Why it is important to do this review

Specic immunotherapy is a disease-modifying treatment, which reduces symptoms in people with AR and asthma (Abramson 2003; Calderon 2007; Dahl 2007; Didier 2007; Penagos 2008). Although SLIT might be potentially effective in reducing allergic ocular symptoms (Durham 2007a; Mortemousque 2003), we are unclear whether these effects are observed consistently across studies. An evaluation of its effects on ocular symptoms in the context of RCTs could provide an alternative treatment for people with AC.
Description of the intervention

Sublingual immunotherapy (SLIT) has been demonstrated to be clinically effective. It is safe and provides an antigen-specic protective immune effect observed in several randomised controlled trials (RCTs) including patients with allergic rhinitis (AR) (Radulovic 2010; Wilson 2005). In recent years, several RCTs evaluating the efcacy of SLIT for allergic rhinoconjunctivitis (ARC) have addressed its particular effect on ocular symptoms. A significant reduction in eye symptoms, conjunctival sensitivity, ocular rescue medication requirements and an improvement in rhinoconjunctivitis quality of life questionnaire scores (RQLQ) have been reported in a study using SLIT with grass pollens (Durham 2007a) and house dust mites (Mortemousque 2003). Regarding perennial AC, a RCT demonstrated that SLIT effectively increased the antigenic threshold required to obtain a positive conjunctival provocation test to house dust mites (Mortemousque 2003). Despite these observations, it is unclear whether this effect is observed among all available studies.
OBJECTIVES
To evaluate the efcacy of SLIT versus placebo in patients with AC or ARC in improving ocular outcomes.
METHODS
Criteria for considering studies for this review
How the intervention might work

It has been proposed that during SLIT, allergen is captured within the oral mucosa by Langerhans-like dendritic cells. Subsequently,
Types of studies We included randomised, double-masked placebo controlled trials of SLIT.

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Types of participants All patients (children and adults) presenting with AC or ARC were included. People with both seasonal and perennial forms of the disease were included. Types of interventions We included studies using SLIT administered either by drops or tablets compared to placebo. Types of outcome measures We evaluated the effect of interventions on primary and secondary outcomes after at least one pollen season for seasonal allergens and for at least six consecutive months for perennial allergens.
Primary outcomes
See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), Web of Science (Appendix 5), Biosis Previews (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 rst and last authors of potentially eligible studies and The Science Citation Index Expanded (SCIEXPANDED, 1945 to the present) was searched using these names for additional studies 2. Compiled a database of international experts in SLIT 3. Searched bibliographies of identied studies 4. Contacted relevant product manufacturers
1. Total ocular symptom scores

Secondary outcomes
Data collection and analysis
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 sensitivity 4. Combined symptom medication scores
Selection of studies Two authors (MC and MP) independently reviewed titles and abstracts from literature searches for relevant trials for full review. The full text copies of all potentially eligible studies were obtained and subjected to independent review using the inclusion criteria detailed above. At this stage, any study rejected was documented in the Characteristics of excluded studies table. The percentage agreement between the investigators for the assessment of inclusion was reported. We resolved disagreement by discussion between both of the authors; in the case of consensus not being reached, a third author (SRD) was involved and, if necessary, arbitrated (Dawson 2004; Higgins 2011a). Data extraction and management Two authors (MP and MC) independently extracted data using a suitably adapted version of the data extraction form developed by the Cochrane Eyes and Vision Group. We resolved disagreements by discussion between both of the authors; in case of consensus not being 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 the included studies for sources of systematic bias in trials according to the guidelines in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). The agreement of 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).
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Search methods for identication of studies
Electronic searches We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2011, Issue 1, part of The Cochrane Library www.thecochranelibrary.com (accessed 19 January 2011), MEDLINE (January 1950 to January 2011), EMBASE (January 1980 to January 2011), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2011), Web of Science (January 1970 to January 2011), Biosis Previews (January 1979 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 the search for trials. All electronic databases except for SCOPUS, the UK Clinical Trials Gateway and ANZCTR were last searched on 19 January 2011. SCOPUS has ceased to be searched as access to this resource is no longer available. The UK Clinical Trials Gateway search has been superseded by searching global clinic trials registers.
We considered the following domains for assessing risk of bias (The Cochrane Collaborations tool) (Higgins 2011b). 1. Sequence generation: describe the method used to generate the allocation sequence in sufcient detail to allow an assessment of whether it should produce comparable groups. 2. Allocation concealment: describe the method used to conceal the allocation sequence in sufcient detail to determine whether intervention 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 and personnel from knowledge of which intervention a participant received. Provide any information relating to whether the intended masking was effective. 4. Incomplete outcome data: describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. State whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomised participants), reasons for attrition or exclusions where reported, and any re-inclusions in analyses performed by the review authors. 5. Selective outcome reporting: state how the possibility of selective outcome reporting was examined by the review authors, and what was found. 6. Other sources of bias: state any important concerns about bias not addressed in the other domains in the tool. Measures of treatment effect We used Review Manager 5.1 (RevMan 2011) for data analysis and quantitative data synthesis. For continuous data (total and individual symptom scores, ocular medication scores and conjunctival immediate allergen sensitivity), we calculated individual and, if appropriate, pooled statistics as mean differences (MDs) or standardised mean differences (SMDs) with 95% condence 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 environmental allergens exposition and, therefore, usually presents with bilateral symptoms (Bielory 2007a; Jackson 1991). Randomised controlled trials on SLIT efcacy report ocular symptoms in participants as only one score at the ocular level (Murdoch 1998). Consequently, analyses were conducted on individuals rather than eyes. Dealing with missing data We contacted trial authors if details about study design or descriptive statistics for outcomes were not presented in the paper (mean, standard deviation (SD)). If the authors did not respond within a reasonable time (six to eight weeks), we conducted the review based on available information.
Assessment of heterogeneity We tested for inconsistency using the I2 statistic. Substantial heterogeneity was assumed if I2 was greater than 40% (that is more than 40% of the variability in the outcome between trials could not be explained by sampling variation) (Deeks 2011; Higgins 2002; Higgins 2003; Sutton 2008). Assessment of reporting biases We looked for evidence of publication bias graphically using funnel plots and statistically by means of the Begg and the Egger tests, if a sufcient number of trials was identied for the primary outcome (Begg 1994; Egger 1997; Higgins 2011b; Sterne 2001). Data synthesis If there was signicant heterogeneity (I2 > 40%), the randomeffects model was used; otherwise we used the xed-effect model. Subgroup analysis and investigation of heterogeneity In the event of uncovering signicant heterogeneity, we investigated the heterogeneity using subgroup analyses. Our subgroups of 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 the impact of exclusion of studies with lower methodological quality; and (ii) by using different statistical methods (xed-effect and random-effects models).
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies. Results of the search The electronic searches yielded a total of 1361 titles and abstracts (Figure 1). After deduplication, the Trials Search Co-ordinator scanned 946 records and discarded 135 records because they were not relevant to the scope of the review. We screened the titles and
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abstracts of the remaining 811 references. We initially excluded nine reports as not being relevant to the review and then evaluated 109 papers in detail.
Figure 1. Results from searching for studies for inclusion in the review
We identied 57 studies (8.6%) that met the inclusion criteria. Of these, 15 studies did not have extractable data and therefore were not included in the meta-analysis. Forty-two studies (5.1%) had available data to evaluate the efcacy of SLIT on AC and were included 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), design differences (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 other inclusion criteria (n = 1). When an outcome of interest was not reported in the full text version of any of the papers, we contacted the authors to ask them whether the endpoint had been evaluated.
Because some of the studies were primarily designed to evaluate the effects of SLIT on allergic rhinitis, 12 authors stated that ocular outcomes were not measured. Included studies Characteristics of the 42 included trials are provided in Table 1. Thirty-eight studies were conducted in Europe, one in both Europe and Canada, one in China, one in Turkey and one in Canada. Of the 42 included studies, 40 (95%) were published in English, one (2.5%) in Chinese and one (2.5%) in Spanish. Eleven studies were published between 1994 and 1999, 13 from 2000 to 2005 and 18 from 2006 up to the last search.
Table 1. Characteristics of included randomised, double-masked, placebo controlled studies Study Year Participants age Mean age or n range randomised 110 Allergen Allergen type Seasonal Presentation Tx duration (months) 6.5
Andre
2003
Children and 35.1 adults Adults 34.8
Ragweed
Both
Ariano
2001
20
Cupressus ari- Seasonal zonica Mites Ambrosia eliator Grass mix Phleum pratense Mites Perennial Seasonal
Drops
Aydogan Bowen
2007 2004
Children
7.28
18 83
Drops Drops
12 3
Children and 36 adults Children Children 9.6 10.1
Bufe Bufe
2004 2009
161 253
Seasonal Seasonal
Drops Tablets
12 7
Cao Casanovas
2007 1994
Children Adults Adults
8.2 25 36.5
278 15 634
Perennial
Drops Drops Tablets
6 4 5
Olea europaea Seasonal Phleum pratense Phleum pratense Grass mix Seasonal
Dahl Allergy 2006
Dahl JACI
2006
Adults
34.5
114
Seasonal
Tablets
de Blay
2007
Children and 24.9 adults
118
Seasonal
Drops
10
10
Table 1. Characteristics of included randomised, double-masked, placebo controlled studies
(Continued)
Didier Dubakiene
2007 2003
Adults
29
628 119
Grass mix Tree pollen
Seasonal Seasonal
Tablets Drops
5 4
Children and 10-61 adults Adults 36
Durham
2006
855
Phleum pratense Grass mix Mites Betula alba Birch pollen
Seasonal
Tablets
4.5
Feliziani Hirsch Horak Khinchi La Rosa
1995 1997 1998 2004 1999
Adults Children Adults Adults Children
14-48 11 33 30 10
34 30 41 71 41
Seasonal Perennial Seasonal Seasonal
Drops Drops Drops Drops Drops
4 12 24 36 24
Parietaria ju- Seasonal daica Olea europaea Seasonal
MorenoAncillo Mortemousque Ott
2007
Children and 28.6 adults Children and 24 adults Children and 33.3 adults Adults 30.3
105
Drops
2003
60
Mites
Perennial
Drops
24
2009
213
Grass mix
Seasonal
Drops
36
PalmaCarlos Panzner
2006
33
Grass mix
Seasonal
Tablets
24
2008
Children and 19.5 adults Children and 27.2 adults Adults 33.2
74
Grass mix
Seasonal
Drops
12
Passalacqua
1998
20
Mites
Perennial
Tablets
24
Passalacqua
1999
30
Parietaria ju- Seasonal daica Mites Grass mix Grass mix Perennial Seasonal Seasonal
Drops
Passalacqua Pfaar Pradalier
2006 2008 1999
Adults Adults
31.2 33.8
68 185 126
Tablets Drops Drops
24 24 4.5
Children and 29.7 Adults Adults 32
Purello-D Ambrosio
1999
30
Parietaria ju- Seasonal daica
Drops
11
Table 1. Characteristics of included randomised, double-masked, placebo controlled studies
(Continued)
RolinckWerninghaus Rder SanchezPalacios Smith Torres-Lima
2004
Children
3-14
97
Grass mix
Seasonal
Drops
32
2007 2001
Children Adults
12.9 24.5
204 40
Grass mix Cat
Seasonal Perennial
Drops Drops
24 12
2004 2002
Adults Adults
40 34
180 56
Grass mix Phleum pratense
Seasonal Seasonal
Both Drops
24 18
Troise
1995
Adults
34.8
31
Parietaria ju- Seasonal daica Tree pollen Juniperus ashei Tree pollen Seasonal Seasonal
Drops
10
Valovirta Vervloet
2006 2007
Children Adults
9 39
98 76
Drops Drops
19 4
Voltolini Vourdas Wahn Wuthrich
2001 1998 2008 2003
Adults Children Children Children
39 12 10.9 7.9
30 66 278 28
Seasonal
Drops Drops Tablets Drops
12 24 5 24
Olea europaea Seasonal Grass mix Grass mix Seasonal Seasonal
Thirty-ve (88%) of the included studies evaluated the efcacy of seasonal allergens and seven trials were with perennial allergens (12%). Nineteen (45%) used grass pollen extracts, 10 (24%) trials evaluated tree pollen extracts, six (14.5%) mites, six (14.5%) weeds and one (2%) was a study assessing the efcacy of a standardised cat extract. All studies compared SLIT with placebo during a doublemasked treatment. Thirty-one (74%) studies administered the extracts as sublingual drops, nine (21%) as tablets and two (5%) both drops during the build-up phase and tablets subsequently for maintenance. A total of 3958 participants with a median age of 29.7 years were treated for a median duration of 12 months (range 3 to 36). Sublingual immunotherapy was given to 2011 (50.8%) participants and placebo to 1947 (49.2%). Two studies (Torres-Lima 2002; Wuthrich 2003) were included in the systematic review but not in the pooled analyses; this was because 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 outcomes. All the authors were contacted and if the information was not available, the study was excluded from the meta-analysis but included in the systematic review.
Risk of bias in included studies

The Cochrane tool was used in this review to assess the risk of bias of the included studies. All the studies were reviewed independently by two authors (MC and MP) and then the evaluations were compared. We resolved disagreements by discussion. Consultation with a third author (SRD or AS) was requested when necessary. A methodological quality summary (Figure 2) and a graph are presented (Figure 3).
12
Figure 2. Methodological quality summary: review authors judgements about each methodological quality item for each included study.
13
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 the allocation sequence (50%) and 12 trials described the methods used to conceal the allocation sequence (29%). Blinding Thirty-eight studies (91%) described the measures used to mask study participants and personnel from knowledge of which intervention a participant received. Incomplete outcome data Forty studies (95%) described the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. Selective reporting For 40 studies (95%) we stated how the possibility of selective outcome reporting was examined by the review authors and what was found. Other potential sources of bias For 33 studies (79%) we stated any important concerns about bias not addressed in the other domains in the tool. As an additional
source of bias in the meta-analytic process, we found that most studies, that is 22 out of 36 reporting total symptom scores, had skewed data in the treatment group (n = 12), in the control group (n = 2), or both (n = 8). Skewness was identied as a mean total symptom score inferior to one SD, nil being the lowest possible value (Deeks 2011). Although in some individual studies data were analysed correctly, that is using non-parametric tests, the need to input skewed data, expressed as mean and SD, in the meta-analysis may limit the validity of our ndings (Cochrane open learning material 2002). Skewness was also found in 14/28 studies for itchy gritty eyes, 19/21 studies for watery eyes, 18/20 studies for red eyes, and 11/13 studies for ocular medication scores.
Effects of interventions
See: Summary of ndings for the main comparison Sublingual immunotherapy versus placebo for allergic conjunctivitis
Effects of SLIT on total ocular symptom scores Thirty-six of the included trials assessed this outcome. Of 3399 participants, 1725 received SLIT and 1674 placebo. Sublingual immunotherapy induced a signicant reduction in total ocular symptom scores compared to placebo (SMD -0.41; 95% CI - 0.53 to - 0.28; P < 0.00001). Substantial inter-study heterogeneity was found (I2 = 59%) (Analysis 1.1).
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Assessment according to the allergen type for those studies using SLIT with seasonal allergens (n = 30) showed a signicant reduction in total ocular symptom scores compared to placebo (SMD -0.38; 95% CI -0.50 to -0.25; P < 0.00001; I2 = 58%) but not perennial 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 studies including 2542 participants (SLIT = 1304 and placebo = 1238) showed a signicant 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 = 421 and placebo = 436) also showed a signicant reduction in total ocular 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 of treatment was evaluated. Twenty-six studies that gave treatment for 12 months or less, including 2888 participants (SLIT = 1468 and placebo = 1420), showed a signicant reduction in total ocular symptom scores (SMD -0.40; 95% CI - 0.53 to - 0.27; P < 0.00001; I2 = 58%). Ten trials gave treatment for 13 months or more, including 511 participants (SLIT = 257 and placebo = 254), and showed a signicant reduction in total ocular symptom scores (SMD -0.43; 95% CI - 0.76 to - 0.10; P = 0.01; I2 = 68%) (Analysis 1.12).
0.23; 95% CI -1.19 to 0.72; P = 0.63). Inter-study inconsistency was signicant (I2 = 83%) (Analysis 1.5). Effects of SLIT on combined symptom medication scores Three studies reported combined symptom medication scores as an outcome; 351 participants were analysed. Sublingual immunotherapy was given to 176 participants and 175 received placebo. There was a marginal non-signicant reduction in the combined scores in those patients receiving SLIT (SMD -0.21; 95% CI -0.55 to 0.13; P = 0.22). Inconsistency among studies was signicant (I2 = 59%) (Analysis 1.7). In two studies this was the primary ocular outcome and total ocular symptom scores were not reported (Bufe 2004; Pfaar 2008). Effects of SLIT on ocular medication scores Thirteen trials including 1038 participants reported the use of eye drops; 560 received SLIT and 478 were treated with placebo. There were not signicant differences between the interventions (SMD -0.10; 95% CI -0.22 to 0.03; P = 0.13). No signicant inter-study inconsistency was found (I2 = 34%) (Analysis 1.6). Effects of SLIT on the conjunctival immediate allergen sensitivity Four trials including 250 participants evaluated this outcome. Sublingual immunotherapy was given to 130 participants and 120 received placebo. Those participants in the active treatment showed an increase in the threshold dose for the conjunctival allergen provocation test (SMD 0.35; 95% CI 0.00 to 0.69; P = 0.05). No signicant inter-study inconsistency was found (I2 = 43%) (Analysis 1.8). Analysis of publication bias
Effects of SLIT on individual ocular symptom scores Itchy gritty eyes: 28 trials evaluated this outcome in 3020 participants (1540 SLIT and 1480 placebo). The overall effect across these trials was a signicant reduction in eye itchiness in the participants treated with SLIT (SMD -0.31; 95% CI -0.42 to -0.20; P < 0.00001). No signicant inter-study heterogeneity was found (I2 = 46%). For two studies, this was the primary ocular outcome and data for total ocular symptom scores were not reported (Passalacqua 2006; Rder 2007) (Analysis 1.2). Watery eyes: 21 studies assessed the efcacy of both SLIT and placebo in 2641 participants; 1344 received SLIT and 1297 placebo. There was a signicant reduction in watery eyes in those participants 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 redness as an outcome. Six hundred and twenty-four participants received SLIT and 587 placebo. The overall effect across these trials showed a signicant reduction in the scores of the participants treated with SLIT (SMD -0.33; 95% CI -0.45 to -0.22; P < 0.00001). No signicant inter-study inconsistency was found (I2 = 27%) (Analysis 1.4). Ocular swelling: only two studies reported ocular swelling as an outcome. One hundred and thirty-two participants were considered of which 66 received SLIT and 66 received placebo. No difference in effect was observed between the treatments (SMD -
Studies excluded for unavailable data We excluded 14 out of 54 trials which met the inclusion criteria as no data were available for them.
Funnel plots To test for the possibility of publication bias in the review, funnel plots were created for total ocular symptom scores. These plots were reasonably symmetrical and there did not appear to be a paucity of smaller trials with small or absent symptoms reduction effect (Figure 4).
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Figure 4. Funnel plot of comparison: 1 Sublingual immunotherapy versus placebo, outcome: 1.1 Total ocular symptom scores.
Eggers and Beggs tests The analysis of small study bias for total ocular symptom scores using the Eggers test was not statistically signicant (P = 0.144). However, the Beggs test showed a signicant publication bias (P = 0.007). Both tests were not signicant in other analyses.
A post hoc tertile analysis was done to determine the effect of the year of publication of trials on the efcacy of SLIT. This analysis was done for all trials evaluating total ocular symptom scores ( Analysis 1.11). The SMD of the latest tertile (2006 to 2009) was compared with that of the earliest tertile (1994 to 1999); there was no signicant difference for total symptom scores between them. Sensitivity analysis
Tertile analysis based on publication year
Sensitivity analyses were performed to assess the robustness of the results, which were unchanged whether the xed-effect model or random-effects model was used (Analysis 1.13 and Table 2).
Table 2. Sensitivity analysis using the random-effects and the xed-effect models Outcome Subgroup or Studies n Random-effects model Fixed-effect model
I2 1.1 Total ocular 36 symptom scores 3399 59%
SMD, 95% CI
I2
SMD, 95% CI -0.38 (-0.44 to -0.31)
-0.41 (-0.53 to -0.28) 59%
16
Table 2. Sensitivity analysis using the random-effects and the xed-effect models
(Continued)
1.2 Itchy/gritty 28 eyes 1.3 Watery eyes 1.4 Red eyes 1.5 Swollen eyes 1.6 Eye drops 21 20 2 13
3020
45%
-0.31 (-0.42 to -0.20) 46%
-0.32 (-0.40 to -0.25)
2641 1211 132 1038 351
42% 27% 83% 34% 59%
-0.23 (-0.34 to -0.11) 42% -0.34 (-0.48 to -0.20) 27% -0.23(-1.19 to 0.72) -0.12 (-0.28 to 0.04) -0.21 (-0.55 to 0.13) 83% 34% 59%
-0.27 (-0.34 to -0.19) -0.33 (-0.45 to -0.22) -0.03 (-0.38 to 0.32) -0.10 (-0.22 to 0.03) -0.21 (-0.42 to 0.00)
1.7 Combined 3 symptom-medication scores 1.8 Conjunctival 4 immediate allergen sensitivity
250
43%
0.35 (0.00 to 0.69)
43%
0.30 (0.05 to 0.55)
DISCUSSION
The present systematic review demonstrates that SLIT is effective in reducing ocular symptoms in people with AC with or without rhinitis. Even though early trials evaluating the effects of specic immunotherapy did not particularly focus on symptoms of conjunctivitis, more recent studies have pointed out the improvement in ocular signs and symptoms when these have been evaluated as a separate outcome. Randomised, double-masked placebo controlled trials evaluating the efcacy of subcutaneous immunotherapy have shown signicant reductions in conjunctival symptoms in individuals with seasonal ARC (Calderon 2007). The study conducted by Dolz et al assessed the efcacy of a grass pollen allergen extract in participants with SAR. After three continuous years of treatment, those patients who received the injective immunotherapy presented lower conjunctival scores compared with those participants receiving placebo (P < 0.001). Moreover, the concentration of antigen necessary to make the test positive increased by 250 BU/ml in the treated group (P < 0.01), while no changes were seen in the placebo group (Dolz 1996). Similar gures were observed by Frew 2006 in a comparison of an extract of Phleum pratense, standardised in SQ units, versus placebo in 410 participants with SAR. Across the whole 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 placebo group. These ndings were summarised in the meta-analysis by Calderon et al, evaluating both nasal and conjunctival outcomes in people with SAR treated with subcutaneous immunotherapy (Calderon 2007). Sublingual immunotherapy has emerged as an effective alternative to subcutaneous immunotherapy. The indications are similar and, where both treatments are available, patient preference becomes an important determinant of choice (Durham 2007b). Recently, a subsequent analysis of a large double-masked placebo controlled trial of a sublingual grass allergen tablet investigated the effect of SLIT on individual eye and nasal symptoms (Dahl 2006b; Durham 2007). Six hundred and thirty-four participants with rhinoconjunctivitis due to grass pollen were randomised 1:1 to receive SLIT (n = 316) or placebo (n = 318) for at least 16 weeks prior to and continued during the grass pollen season. Consistent and highly signicant reductions in individual eye and nasal symptoms (from 22% to 44%) were observed following treatment with SLIT compared with placebo. For eye symptoms, the score for the actively treated group was reduced in 36% as compared with placebo (P < 0.0001). A separation of the eye symptoms into individual symptoms also showed consistently lower symptom scores in the immunotherapy group. The percentage reductions relative to placebo were -32% for gritty eyes (P < 0.0001) and 44% for watery eyes (P < 0.0001) (Durham 2007). Motivated by these sta-
17
tistically signicant results, we decided to carry out the current review. This systematic review identied 54 randomised double-masked placebo controlled trials meeting the inclusion criteria. After a detailed evaluation of the papers and having made requests to the authors for unpublished data, 40 of these trials were included in the meta-analysis. Two studies (Torres-Lima 2002; Wuthrich 2003) were included in the systematic review but not meta-analysed as the raw data provided were not comparable with the pooled data. Forty-one studies evaluated the ocular symptoms in patients with rhinoconjunctivitis and one study was designed specically to assess the effect of SLIT in allergic perennial conjunctivitis (Mortemousque 2003). The current systematic review and meta-analysis conrms that SLIT signicantly 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 watery eyes (SMD -0.23; P = 0.0001) in patients with rhinoconjunctivitis. These observed effect sizes for SLIT over placebo compare favourably with those observed in recent large, randomised, double-masked placebo controlled trials (Dahl 2006b; Didier 2007). These reductions were evident when the studies assessed seasonal allergens (SMD -0.38; 95% CI -0.50 to -0.25; P < 0.00001) but not perennial (SMD -0.52; 95% CI -1.05 to 0.01; P = 0.05). These differences could be explained by the paucity of studies evaluating perennial allergens (n = 6) and the small numbers of participants analysed for this outcome (SLIT 109 versus placebo 110) (Analysis 1.9). When the combined symptom medication scores were evaluated, a marginal, non-signicant reduction in SMD was evident, but only three studies assessing 351 participants were included (Analysis 1.8). Sublingual immunotherapy in children induced a signicant reduction in the primary outcome after pooling the nine studies that exclusively included participants aged four to 17 years. The SMD for 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 signicant reduction in total ocular symptom scores in those patients receiving SLIT (Bufe 2008; Wahn 2009). The SMD for symptom reductions in adults 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 not affect 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 difcult to assess due to the fact that most of the studies evaluated diverse schedules of treatment, different types of allergens, and the timing of treatment was variable with respect to pollen seasons. Other factors such as the
frequency of administration of the SLIT and the continuity of the treatment out of season may also affect outcomes (Analysis 1.12). Previous meta-analyses have demonstrated reductions in medication scores in people receiving SLIT (Penagos 2006; Penagos 2008; Wilson 2005). The participants in large studies also used significantly 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 nd a signicant effect 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 be explained by the fact that participants generally are instructed to use intranasal steroids and take systemic antihistamines as rescue medications. These medications are easy to take and both have been demonstrated to be effective in reducing ocular symptoms in patients with ARC. In a recent retrospective pooled analysis of four RCTs of patients with SAR, mometasone furoate nasal spray 200 g once daily proved to be effective in reducing morning and evening total ocular symptom scores and the individual ocular symptom scores compared with placebo (Bielory 2008b). Another retrospective analysis of four RCTs, evaluating the efcacy of uticasone furoate nasal spray (FFNS) in patients with ARC, provided evidence of signicant reductions in the reective total ocular symptom scores in those patients treated with FFNS compared with placebo (Scadding 2008). The mechanism by which an intranasal corticosteroid reduces ocular allergic symptoms has been under investigation and some effects on both the reex neural activity and the local inammation, facilitating the nasolacrimal drainage, have been proposed (Bielory 2007b; Bielory 2008b). Baroody 2009 conducted a double-masked, placebo controlled randomised, crossover experiment in 20 people with seasonal AR. A localised and unilateral nasal challenge with grass or ragweed extracts was performed consecutively for three days after one week of treatment with either placebo or FFNS. A nasal challenge led to sneezing and a nasonasal reex, which increased after three repetitive antigen challenges, demonstrating priming. Ocular symptoms also increased after each nasal challenge with antigen, supporting the existence of a nasal-ocular reex response and its ability to prime in response to nasal inammation. Treatment with FFNS reduced sneezing, the nasonasal and nasal-ocular reexes, ocular symptoms and the amount of eosinophils in nasal secretions. The authors postulated that reductions in both allergic inammation and the nasal-ocular reex provide a potential mechanism to explain how treatment with an intranasal steroid may work locally in the nose to reduce the ocular symptoms associated with AR. Additionally, antihistamines such as desloratadine and levocetirizine have shown reductions in individual ocular symptoms following allergen conjunctival challenges or continuous treatment for AR, respectively (Canonica 2008; Torkildsen 2009). Regarding the allergen dose, available evidence especially that derived from large comparisons evaluating diverse dosages of pollen extracts has demonstrated that the efcacy is related to the daily
18
amount of allergen administered (Dahl 2006b; Didier 2007; Durham 2006; Valovirta 2006). Meta-analyses are not the best methods to determine the effect of the allergen dose on the clinical outcomes. This is due to the diversity of allergen preparations used, variable daily and cumulative doses, and the lack of information in some studies regarding the dose of the major allergen expressed in a common unit (g). According to The Cochrane Collaboration, other statistical methods are available to assess this relationship, such as meta-regression. However, the ideal way of looking at the effect of dose would be to have randomised trials comparing the doses (head-to-head comparisons) (Calderon 2008; Higgins 2011a). The risk of severe systemic reactions, including anaphylaxis, has been a key concern in relation to SLIT. Encouragingly, no treatment-related severe systemic adverse events requiring intervention with adrenaline has occurred during diverse large-scale randomised multicentre trials using SLIT (Durham 2008; Radulovic 2007b). Even though our analysis was not designed to assess safety, the examined trials consistently described the large majority of adverse effects as mild and self-resolving, in accordance with previous reviews. We identied some studies with design limitations, lack of sample size calculations and poor measures to prevent bias. These studies, basically published earlier, did not follow the Consolidated Standards of Reporting Trials (CONSORT) statement for the publication of RCTs. This made the identication of key information regarding randomisation methods and concealment of allocation difcult. On the other hand, publication bias is an important drawback of systematic reviews and it is difcult to avoid. Although we searched for articles in the most important electronic databases of medical information, in abstract books from relevant meetings and in the most diffuse languages, it is possible that not all the studies have been found. The analyses of publication bias for total ocular symptom scores using the funnel plot analysis and the Eggers test did not show a statistical signicant bias. However, signicant bias was detected using the Beggs test. We recognise that these ndings are inconclusive in relation to the possibility of publication bias and that there is a risk of selective reporting in some studies and the GRADE score has therefore been downgraded accordingly (Summary of ndings for the main comparison). We encourage authors to publish negative results studies to allow researchers to avoid publication bias. We identied some possible sources of bias in the present metaanalysis as some outcomes presented a degree of inter-study inconsistency (heterogeneity); studies with low statistical power were included; and some outcomes included small numbers of studies (Higgins 2011a). Heterogeneity between studies was signicant in this review, resulting largely from methodological and clinical heterogeneity (that is differences in scoring systems; sample sizes; type, schedule and dose of allergen; age groups; treatment duration; disease severity) across studies. As a consequence, we de-
creased the quality of evidence according to GRADE (Summary of ndings for the main comparison). Moreover, we recognise the fact that data were skewed in relation to a number of studies that were included in this review and we therefore suggest that the ndings from our meta-analyses be interpreted with caution. This review has several strengths, such as the restrictive inclusion criteria for the studies, the statistically signicant effect size found according to Cohens criteria, the robust statistical methods to control both inter- and intra-study variability and the quantitative approach carried out. Moreover, most of the analysed data were provided by the authors. We need more well-designed and powered studies assessing the impact on quality of life and cost-effectiveness and head-to-head studies with other treatment regimens. We identied 14 randomised, parallel-group, double-masked and placebo controlled clinical trials in an international clinical trials registry (http:// clinicaltrials.gov/) which are currently in progress. Their data were not available for inclusion in this review. A better understanding of the long-term effectiveness of SLIT in inducing tolerance is also required. In conclusion, SLIT has effects on multiple allergic symptoms, including ocular symptoms, and is effective in the treatment of rhinoconjunctivitis.
Summary of main results

This comprehensive review identied 811 studies from which only 42 trials were included in the analysis. The current evidence suggests benecial effects of specic allergen immunotherapy in reducing 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. Sublingual immunotherapy signicantly reduced both total ocular symptom scores and individual ocular symptoms scores (redness, itchiness and watery eyes) compared to placebo. The pooled estimates suggested, however, that SLIT is likely to have a small to moderate effect in AC-related ocular symptoms.
Overall completeness and applicability of evidence

The 42 included studies enrolled over 3958 participants with AC. The participants in all the included trials were selected based on objective conrmation of their atopic status and the clinical manifestation of the allergic disease. Most of the studies reported adequately on the age and sex of the participants, the allergen causing disease and disease severity. Therefore the participants were representative of patients with AC, which enhances the generalisability of our ndings.
Quality of the evidence

19
All trials in this review had the same study design and we included those studies evaluating the same clinical outcomes. The distribution of participants between the therapeutic intervention, receiving SLIT (n = 2011), and placebo (n = 1947) was well-proportioned. Heterogeneity among studies (I2 statistic) was around 50% or below for all endpoints. This applies for all outcomes except for swollen eyes (I2 = 83%); however this outcome was assessed in only two studies. Subgroup analysis for total ocular symptom scores did not decrease statistical heterogeneity, therefore we cannot rule out that the moderate heterogeneity observed for this outcome is due to a true variability of effects in the studies, or due to methodological variability (for example the measurement tools used to obtain the total symptom score). A key methodological limitation is the small sample size of most of the studies (56% had less than 30 participants per arm). In this review, only 17% included more than 100 participants in each arm, 8% up to 50 and 19% up to 30 participants. Some trials did not adequately describe their method of randomisation or allocation concealment thus precluding formal assessment of the likelihood of selection bias.
therefore, comparisons with other reviews cannot be made.
AUTHORS CONCLUSIONS Implications for practice

This rigorously conducted review of a substantive body of trial evidence has found that SLIT is overall effective in reducing ocular symptoms in people with ARC. Clinical interpretation of the effectiveness of SLIT in reducing symptoms, which was expressed as the standardised mean difference, can be difcult, but is comparable to that observed in previous Cochrane reviews of SLIT for nasal symptoms. The overall quality of the evidence was assessed to be low to moderate due in part to limitations with the description of allocation concealment in some studies, moderate statistical heterogeneity and possible publication bias. In summary, this review provides evidence that once daily treatment with SLIT in the form of either drops or sublingual tablets represents a treatment option in patients with AC and ARC with ocular symptoms.
Potential biases in the review process

By using the Cochrane risk of bias tool we identied that only 50% of the included trials reported an adequate sequence generation; 90% described the methods to mask the interventions; 95% addressed incomplete outcome data; 95% were considered free of selective reporting and 79% were free of other bias. It is important to mention that only 29% of the studies provided a description of the allocation concealment methods. Due to the nature of the disease, the majority of the studies aimed to treat rhinoconjunctivitis and not the ocular component by itself; only one study was specically designed to evaluate just conjunctivitis. However, in all the studies eye symptom scores were planned to be assessed as a primary or secondary endpoint. Limitations of this review are moderate heterogeneity and potential publication bias. Finally, the clinical relevance of the benet regarding the primary outcome total symptom score is not intuitive, given the use of SMD in our review. Based on a common rule of thumb, also mentioned in the Cochrane Handbook for Systematic Reviews of Interventions (Patrick 2008), for our primary outcome the observed effect size (SMD -0.41; 95% CI - 0.53 to - 0.28) ranges between a small and moderate benet.
Implications for research

Further large denitive trials are required as well as head-to-head comparative studies with currently available anti-allergic drugs. Whether SLIT may result in long-term benets after discontinuation of therapy is an important question that warrants further evaluation. There is a paucity of pharmaco-economic evaluations and such studies are also necessary to help clarify the place of SLIT in comparison with other treatment options. Further studies evaluating the mechanisms of SLIT are needed. There is also a need to develop and validate standard instruments, such as questionnaires with adequate psychometrical properties, in this eld of research, which would also make future studies more comparable and adequate for meta-analysis.
ACKNOWLEDGEMENTS
We thank Anupa Shah, Managing Editor for the Cochrane Eyes and Vision Group (CEVG) for all her support. We acknowledge the CEVG Trials Search Co-ordinator, Iris Gordon, for devising and running the electronic searches. We thank the Co-ordinating Editor, Richard Wormald, for his assistance and comments. We are grateful to Dr Gianni Virgili for his invaluable statistical support. We thank Leonard Bielory and Catey Bunce for their comments on the review. We are thankful to Dr Chen Ji and Dr Guo Yifeng for their help in translating the paper published in Chinese.
Agreements and disagreements with other studies or reviews

To our knowledge, this is the rst systematic review on this topic;
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REFERENCES
References to studies included in this review

Andre 2003 {published and unpublished data} Andr C, Perrin-Fayolle M, Grosclaude M, Couturier P, Basset D, Cornillon J, et al.A double-blind placebocontrolled evaluation of sublingual immunotherapy with a standardized ragweed extract in patients with seasonal rhinitis. Evidence for a dose-response relationship. International Archives of Allergy and Immunology 2003;131 (2):1118. Ariano 2001 {published and unpublished data} Ariano R, Spadolini I, Panzani RC. Efcacy of sublingual specic immunotherapy in Cupressaceae allergy using an extract of Cupressus arizonica. A double blind study. Allergologia et Immunopathologia 2001;29(6):23844. 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 development of asthma in children with allergic rhinitis sensitised to house-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 sublingual swallow immunotherapy for ragweed rhinoconjunctivitis. Annals of Allergy, Asthma & Immunology 2004;93(5): 42530. Bufe 2004 {published and unpublished data} Bufe A, Ziegler-Kirbach E, Stoeckmann E, Heidemann P, Gehlhar K, Holland-Letz T, et al.Efcacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double-blind placebo-controlled study. Allergy 2004;59(5):498504. 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 for sublingual Immunotherapy in children. Journal of Allergy and 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, et al.Clinical evaluation for sublingual immunotherapy of allergic asthma and atopic rhinitis with dermatophagoides farinae drops. Zhonghua Er Ke Za Zhi 2007;45(10):73641. Casanovas 1994 {published and unpublished data} Casanovas M, Guerra F, Moreno C, Miguel R, Maran F, Daza JC. Double-blind, placebo-controlled clinical trial of preseasonal treatment with allergenic extracts of Olea europaea pollen administered sublingually. Journal of Investigational Allergology & Clinical Immunology 1994;4(6): 30514. Dahl 2006a {published and unpublished data} Dahl R, Stender A, Rak S. Specic immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis. Allergy 2006;61(2):18590.
Dahl 2006b {published and unpublished data} Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, Emminger W, et al.Efcacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. Journal of Allergy and Clinical Immunology 2006;118(2):43440. 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. Sublingualswallow immunotherapy with standardized 3-grass pollen extract: a double-blind, placebo-controlled study. Annals of Allergy, Asthma & Immunology 2007;99(5):45361. Didier 2007 {published and unpublished data} Didier A, Malling HJ, Worm M, Horak F, Jger S, Montagut A, et al.Optimal dose, efcacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. Journal of Allergy and Clinical Immunology 2007;120(6):133845. Dubakiene 2003 {unpublished data only} Dubakiene R, Kleinjans HAJ. Effectiveness of Specic Sublingual IT (SLIT) with tree pollen. A placebo controlled study in 119 patients. XXII Congress of the European Academy 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 grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. Journal of Allergy and Clinical Immunology 2006;117(4):8029. Feliziani 1995 {published and unpublished data} Feliziani V, Lattuada G, Parmiani S, DallAglio PP. Safety and efcacy of sublingual rush immunotherapy with grass allergen extracts. A double blind study. Allergologia et Immunopathologia 1995;23(5):22430. Hirsch 1997 {published and unpublished data} Hirsch T, Shn M, Leupold W. Double-blind placebocontrolled study of sublingual immunotherapy with house dust mite extract (D.pt.) in children. Pediatric Allergy and Immunology 1997;8(1):217. Horak 1998 {published and unpublished data} Horak F, Stbner P, Berger UE, Marks B, Toth J, Jger S. Immunotherapy with sublingual birch pollen extract. A short-term double-blind placebo study. Journal of Investigational Allergology & Clinical Immunology 1998;8(1): 16571. Khinchi 2004 {published and unpublished data} Khinchi MS, Poulsen LK, Carat F, Andr C, Hansen AB, Malling HJ. Clinical efcacy of sublingual and subcutaneous birch pollen allergen-specic immunotherapy: a randomized, placebo-controlled, double-blind, doubledummy study. Allergy 2004;59(1):4553.
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La Rosa 1999 {published and unpublished data} La Rosa M, Ranno C, Andr C, Carat F, Tosca MA, Canonica GW. Double-blind placebo-controlled evaluation of sublingual-swallow immunotherapy with standardized Parietaria judaica extract in children with allergic rhinoconjunctivitis. Journal of Allergy and Clinical Immunology 1999;104(2 Pt 1):42532. Moreno-Ancillo 2007 {published and unpublished data} Moreno-Ancillo A, Moreno C, Ojeda P, Domnguez C, Barasona MJ, Garca-Cubillana A, et al.Efcacy and quality of life with once-daily sublingual immunotherapy with grasses plus olive pollen extract without updosing. Journal of Investigational Allergology & Clinical Immunology 2007; 17(6):399405. Mortemousque 2003 {published and unpublished data} Mortemousque B, Bertel F, De Casamayor J, Verin P, Colin J. House-dust mite sublingual-swallow immunotherapy in perennial conjunctivitis: a double-blind, placebo-controlled study. Clinical and Experimental Allergy 2003;33(4):4649. Ott 2008 {published data only} Ott H, Sieber J, Brehler R, Flster-Holst R, Kapp A, Klimek L, et al.Efcacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study. Allergy 2009;64(9):17986. Palma-Carlos 2006 {published and unpublished data} Palma-Carlos AG, Santos AS, Branco-Ferreira M, Pregal AL, Palma-Carlos ML, Bruno ME, et al.Clinical efcacy and safety of preseasonal sublingual immunotherapy with grass pollen carbamylated allergoid in rhinitic patients. A double-blind, placebo-controlled study. Allergologia et Immunopathologia 2006;34(5):1948. Panzner 2008 {published data only} Panzner P, Petrs M, Skora T, Lesn I. Double-blind, placebo-controlled evaluation of grass pollen specic immunotherapy with oral drops administered sublingually or supralingually. Respiratory Medicine 2008;102(9): 12961304. Passalacqua 1998 {published data only} Passalacqua G, Albano M, Fregonese L, Riccio A, Pronzato C, Mela GS, et al.Randomised controlled trial of local allergoid immunotherapy on allergic inammation in miteinduced rhinoconjunctivitis. Lancet 1998;351(9103): 62932. Passalacqua 1999 {published data only} Passalacqua G, Albano M, Riccio A, Fregonese L, Puccinelli P, Parmiani S, et al.Clinical and immunologic effects of a rush sublingual immunotherapy to Parietaria species: A double-blind, placebo-controlled trial. Journal of Allergy and Clinical Immunology 1999;104(5):9648. Passalacqua 2006 {published data only} Passalacqua G, Pasquali M, Ariano R, Lombardi C, Giardini A, Baiardini I, et al.Randomized double-blind controlled study with sublingual carbamylated allergoid immunotherapy in mild rhinitis due to mites. Allergy 2006; 61(7):84954.
Pfaar 2008 {published and unpublished data} Pfaar O, Klimek L. Efcacy and safety of specic immunotherapy with a high-dose sublingual grass pollen preparation: a double-blind, placebo-controlled trial. Annals of Allergy, Asthma & Immunology 2008;100(3): 25663. Pradalier 1999 {published and unpublished data} Pradalier A, Basset D, Claudel A, Couturier P, Wessel F, Galvain S, et al.Sublingual-swallow immunotherapy (SLIT) with a standardized ve-grass-pollen extract (drops and sublingual tablets) versus placebo in seasonal rhinitis. Allergy 1999;54(8):81928. Purello-D Ambrosio 1999 {published and unpublished data} Purello-DAmbrosio F, Gangemi S, Isola S, La Motta N, Puccinelli P, Parmiani S, et al.Sublingual immunotherapy: a double-blind, placebo-controlled trial with Parietaria judaica extract standardized in mass units in patients with rhinoconjunctivitis, asthma, or both. Allergy 1999;54(9): 96873. 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 the efcacy and safety of sublingual immunotherapy (SLIT) in children with seasonal allergic rhinoconjunctivitis to grass pollen. Allergy 2004;59(12):128593. Rder 2007 {published and unpublished data} Rder E, Berger MY, Hop WC, Bernsen RM, de Groot H, Gerth van Wijk R. Sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care. Journal of Allergy and Clinical Immunology 2007;119 (4):8928. Sanchez-Palacios 2001 {published and unpublished data} Snchez Palacios A, Schamann F, Garca JA. Sublingual immunotherapy with cat epithelial extract. Personal experience. Allergologia et Immunopathologia 2001;29(2): 605. Smith 2004 {published and unpublished data} Smith H, White P, Annila I, Poole J, Andre C, Frew A. Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. Journal of Allergy and Clinical Immunology 2004;114(4):8317. Torres-Lima 2002 {published and unpublished data} Torres-Lima M, Wilson D, Pitkin L, Roberts A, NouriAria K, Jacobson M, et al.Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial. Clinical and Experimental Allergy 2002;32(4):50714. Troise 1995 {published and unpublished data} Troise C, Voltolini S, Canessa A, Pecora S, Negrini AC. Sublingual immunotherapy in Parietaria pollen-induced rhinitis: a double-blind study. Journal of Investigational Allergology & Clinical Immunology 1995;5(1):2530. Valovirta 2006 {published data only} Valovirta E, Jacobsen L, Ljrring C, Koivikko A, Savolainen J. Clinical efcacy and safety of sublingual immunotherapy
22
with tree pollen extract in children. Allergy 2006;61(10): 117783. Vervloet 2007 {published and unpublished data} Vervloet D, Birnbaum J, Laurent P, Hugues B, Fardeau MF, Massabie-Bouchat YP, et al.Safety and efcacy of Juniperus ashei sublingual-swallow ultra-rush pollen immunotherapy in cypress rhinoconjunctivitis. A double-blind, placebocontrolled study. International Archives of Allergy and Immunology 2007;142(3):23946. Voltolini 2001 {published data only} Voltolini S, Modena P, Minale P, Bignardi D, Troise C, Puccinelli P, et al.Sublingual immunotherapy in tree pollen allergy. Double-blind, placebo-controlled study with a biologically standardised extract of three pollens (alder, birch and hazel) administered by a rush schedule. Allergologia et Immunopathologia 2001;29(4):10310. Vourdas 1998 {unpublished data only} Vourdas D, Syrigou E, Potamianou P, Carat F, Batard T, Andr C, et al.Double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized olive pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive pollen sensitization. Allergy 1998;53(7):66272. Wahn 2009 {published and unpublished data} Wahn U, Tabar A, Kuna P, Halken S, Montagut A, de Beaumont O, et al. SLIT Study Group. Efcacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. Journal of Allergy and Clinical Immunology 2009;123(1):1606. Wuthrich 2003 {published data only} Wthrich B, Bucher Ch, Jrg W, Bircher A, Eng P, Schneider Y, et al.Double-blind, placebo-controlled study with sublingual immunotherapy in children with seasonal allergic rhinitis to grass pollen. Journal of Investigational Allergology & Clinical Immunology 2003;13(3):1458.
Bahceciler 2005 {published data only} Bahceciler NN, Arikan C, Taylor A, Akdis M, Blaser K, Barlan IB, et al.Impact of sublingual immunotherapy on specic antibody levels in asthmatic children allergic to house dust mites. International Archives of Allergy and Immunology 2005;136(3):28794. Boquete 2006 {published and unpublished data} Boquete M, Rodriguez F, Tabar A, Ibanez D, Nieto A, Torre-Martinez F. Assessment of a new treatment schedule in sublingual immunotherapy. A randomised double-blind placebo-controlled multicentre study. Journal of Allergy and Clinical Immunology 2006;117(2):162. Bordignon 2003 {published data only} Bordignon V, Parmiani S. Variation of the skin end-point in patients treated with sublingual specic immunotherapy. Journal of Investigational Allergology & Clinical Immunology 2003;13(3):1706. Brown 2001 {published data only} Brown JL, Frew AJ. The efcacy of oromucosal immunotherapy in respiratory allergy. Clinical and Experimental Allergy 2001;31(1):810. Burastero 2008 {published data only} Burastero S, Falangiani P, Paolucci C, Breda D, Roncarolo D, Zanotta S, et al.Clinical and immunological correlates of pre-co-seasonal sublingual immunotherapy with birch monomeric allergoid in patients with allergic rhinoconjunctivitis. Allergy 2008;63 Suppl 88:227. Caffarelli 2000 {published data only} Caffarelli C, Sensi LG, Marcucci F, Cavagni G. Preseasonal local allergoid immunotherapy to grass pollen in children: a double-blind, placebo-controlled, randomized trial. Allergy 2000;55(12):11427. Ciprandi 2007 {published data only} Ciprandi G, Alesina R, Ariano R, Borreli P, Cadario G, Capristo A, et al.Sublingual immunotherapy in polysensitized patients: a preliminary study. Allergy 2007; 62 Suppl 83:241. Clavel 1996 {published data only} Clavel R, Andre C, Bousquet J. Reduction of oral corticotherapy by sublingual immunotherapy (IT): doubleblind placebo-controlled study in grass pollen allergy. Journal of Allergy and Clinical Immunology 1996;97(1):232. Clavel 1998 {published data only} Clavel R, Bousquet J, Andr C. Clinical efcacy of sublingual-swallow immunotherapy: a double-blind, placebo-controlled trial of a standardized ve-grass-pollen extract in rhinitis. Allergy 1998;53(5):4938. Di Rienzo 2006 {published data only} Di Rienzo V, Pucci S, DAlo S, Di Cara G, Incorvaia C, Frati F, et al.Effects of high-dose sublingual immunotherapy on quality of life in patients with cypress-induced rhinitis: A placebo-controlled study. Clinical and Experimental Allergy Reviews 2006;6(3):6770.
23
References to studies excluded from this review

Alvarez-Cuesta 2007 {published and unpublished data} Alvarez-Cuesta E, Berges-Gimeno P, Gonzlez-Mancebo E, Fernndez-Caldas E, Cuesta-Herranz J, Casanovas M. Sublingual immunotherapy with a standardized cat dander extract: evaluation of efcacy in a double blind placebo controlled study. Allergy 2007;62(7):8107. Amar 2009 {published data only} Amar SM, Harbeck RJ, Sills M, Silveira LJ, OBrien H, Nelson HS. Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract. Journal of Allergy and Clinical Immunology 2009;124(1):1506. Bahceciler 2001 {published data only} Baheciler NN, Isik U, Barlan IB, Basaran MM. Efcacy of sublingual immunotherapy in children with asthma and rhinitis: a double-blind, placebo-controlled study. Pediatric Pulmonology 2001;32(1):4955.
Didier 2009 {published data only} Didier A, Melac M, Montagut A, Lhritier-Barrand M, Tabar A, Worm M. Agreement of efcacy assessments for ve-grass pollen sublingual tablet immunotherapy. Allergy 2009;64(1):16671. Drachenberg 2001 {published data only} Drachenberg KJ, Pfeiffer P, Urban E. Sublingual immunotherapy - Results from a a multi-centre, randomised, double-blind, placebo-controlled study with standardised birch and grass/rye pollen extract. Allergologie 2001;24(11):52534. Durham 2007 {published data only} Durham SR, Riis B. Grass allergen tablet immunotherapy relieves individual seasonal eye and nasal symptoms, including nasal blockage. Allergy 2007;62(8):9547. Durham 2010 {published data only} Durham SR, Emminger W, Kapp A, Colombo G, de Monchy JG, Rak S, et al.Long-term clinical efcacy in grass pollen-induced rhinoconjunctivitis after treatment with SQstandardized grass allergy immunotherapy tablet. Journal of Allergy and Clinical Immunology 2010;125(1):1318. Esch 2008 {unpublished data only} Esch RE, Bush RK, Skoner D, Gentile D, McLaughlin A, Fasano MB. Parallel, randomized, double-blind, placebocontrolled, dose-response phase IIb trial in adults for short ragweed sublingual-oral immunotherapy (SLIT). Journal of Allergy and Clinical Immunology 2008;121 Suppl 1(2):127. Grosclaude 2002 {published data only} Grosclaude M, Bouillot P, Alt R, Leynadier F, Scheinmann P, Run P, et al.Safety of various dosage regimens during induction of sublingual immunotherapy: A preliminary study. International Archives of Allergy and Immunology 2002;129(3):24853. Guez 2000 {published data only} Guez S, Vatrinet C, Fadel R, Andr C. House-dust-mite sublingual-swallow immunotherapy (SLIT) in perennial rhinitis: a double-blind, placebo-controlled study. Allergy 2000;55(4):36975. Horak 2008 {published data only} Horak F, Siegfried J, Worm M, Melac M, Didier A. Clinical efcacy of sublingual immunotherapy (SLIT) with grass pollen tablets in patients with rhinoconjunctivitis throughout the pollen season and at peak pollen. Allergy 2008;63 Suppl 88:226. Horak 2009 {published data only} Horak F, Jaeger S, Worm M, Melac M, Didier A. Implementation of pre-seasonal sublingual immunotherapy with a ve-grass pollen tablet during optimal dosage assessment. Clinical and Experimental Allergy 2009;39(3): 394400. 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-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber. Journal of Allergy and Clinical Immunology 2009;124(3):4717.
Hordijk 1998 {published data only} Hordijk GJ, Antvelink JB, Luwema RA. Sublingual immunotherapy with a standardised grass pollen extract; a double-blind placebo-controlled study. Allergologia et Immunopathologia 1998;26(5):23440. Horiguchi 2008a {published data only} Horiguchi S, Okamoto Y, Yonekura S, Okawa T, Yamamoto H, Kunii N, et al.A randomized controlled trial of sublingual immunotherapy for Japanese cedar pollinosis. International Archives of Allergy and Immunology 2008;146(1):7684. Horiguchi 2008b {published data only} Horiguchi S, Okamoto Y, Yonekura S, Okawa T, Kunii N, Yamamoto H, et al.Lowered effectiveness of immunotherapy for cypress pollinosis by using Japanese cedar pollen extract. Arerugi 2008;57(5):55861. Ippoliti 2003 {published data only} Ippoliti F, De Santis W, Volterrani A, Lenti L, Canitano N, Lucarelli S, et al.Immunomodulation during sublingual therapy in allergic children. Pediatric Allergy and Immunology 2003;14(3):21621. Kleine-Tebbe 2007 {published data only} Kleine-Tebbe J, Bachert C, Bergmann KC, Bieber T, Brehler R, Friedrichs F, et al.Present role of sublingual immunotherapy in allergic diseases. Allergologie 2007;30: 37888. Lombardi 2005 {published data only} Lombardi C, Passalacqua G, Ariano R, Pasquali M, Baiardini I, Giardini A, et al.A 3-year randomized controlled study with sublingual immunotherapy in mite-induced respiratory allergy. 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, Chou MC. Clinical and immunologic effects of sublingual immunotherapy in asthmatic children sensitized to mites: a double-blind, randomized, placebo-controlled study. Pediatric Allergy and Immunology 2006;17(6):40815. Maestrelli 2004 {published data only} Maestrelli P, Zanolla L, Pozzan M, Fabbri LM. Effect of specic immunotherapy added to pharmacologic treatment and allergen avoidance in asthmatic patients allergic to house dust mite. Journal of Allergy and Clinical Immunology 2004;113(4):6439. Malling 2009 {published data only} Malling HJ, Montagut A, Melac M, Patriarca G, Panzner P, Seberova E, et al.Efcacy and safety of 5-grass pollen sublingual immunotherapy tablets in patients with different clinical proles of allergic rhinoconjunctivitis. Clinical and Experimental Allergy 2009;39(3):38793. Marcucci 2001 {published data only} Marcucci F, Sensi L, Frati F, Senna GE, Canonica GW, Parmiani S, et al.Sublingual tryptase and ECP in children treated with grass pollen sublingual immunotherapy (SLIT): safety and immunologic implications. Allergy 2001;56(11): 10915.
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Marcucci 2003 {published data only} Marcucci F, Sensi L, Frati F, Bernardini R, Novembre E, Barbato A, et al.Effects on inammation parameters of a double-blind, placebo controlled one-year course of SLIT in children monosensitized to mites. Allergy 2003;58(7): 65762. Marcucci 2005a {published data only} Marcucci F, Sensi L, Di Cara G, Incorvaia C, Frati F. Dose dependence of immunological response to sublingual immunotherapy. Allergy 2005;60(7):9526. Marcucci 2005b {published and unpublished data} Marcucci F, Sensi L, Di Cara G, Salvatori S, Bernini M, Pecora S, et al.Three-year follow-up of clinical and inammation parameters in children monosensitized to mites undergoing sub-lingual immunotherapy. Pediatric Allergy and Immunology 2005;16(6):51926. Maria 2004 {published data only} Maria D, Dervaderics M. Long-lasting effect of sublingual ragweed 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 primary multicentric study, specic immunotherapy administered sublingually. TW Padiatrie 1996;9(11-12):62831. Mungan 1999 {published data only} Mungan D, Misirligil Z, Grbz L. Comparison of the efcacy of subcutaneous and sublingual immunotherapy in mite-sensitive patients with rhinitis and asthma--a placebo controlled study. Annals of Allergy, Asthma & Immunology 1999;82(5):48590. Msges 2007 {published data only} Msges R, Brning H, Hessler HJ, Gtz G, Knaussmann HG. Sublingual immunotherapy in pollen-induced seasonal rhinitis and conjunctivitis: a randomized controlled trial. Acta Dermatovenerologica Alpina, Panonica, et Adriatica 2007;16(4):1438. Nelson 1993 {published data only} Nelson HS, Oppenheimer J, Vatsia GA, Buchmeier A. A double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized cat extract. Journal of Allergy and Clinical Immunology 1993;92(2):22936. Niu 2006 {published data only} Niu CK, Chen WY, Huang JL, Lue KH, Wang JY. Efcacy of sublingual immunotherapy with high-dose mite extracts in asthma: a multi-center, double-blind, randomized, and placebo-controlled study in Taiwan. Respiratory Medicine 2006;100(8):137483. Okubo 2008 {published data only} Okubo K, Gotoh M, Fujieda S, Okano M, Yoshida H, Morikawa H, et al.A randomized double-blind comparative study of sublingual immunotherapy for cedar pollinosis. Allergology International 2008;57(3):26575. Pajno 2000 {published data only} Pajno GB, Morabito L, Barberio G, Parmiani S. Clinical and immunologic effects of long-term sublingual
immunotherapy in asthmatic children sensitized to mites: a double-blind, placebo-controlled study. Allergy 2000;55(9): 8429. Pajno 2003 {published data only} Pajno GB, Vita D, Parmiani S, Caminiti L, La Grutta S, Barberio G. Impact of sublingual immunotherapy on seasonal asthma and skin reactivity in children allergic to Parietaria pollen treated with inhaled uticasone propionate. Clinical and Experimental Allergy 2003;33(12):16417. Peter 2009 {published data only} Peter R, Kleinjans H, Hecker H. Signicant increase in IgG4 levels after slit grass treatment. A double-blind, placebo-controlled, multi-center study (Twin Grasses Study). Allergy 2009;64 Suppl 90:3523. Potter 2007 {unpublished data only} Potter P, Nurse B, Hawarden D, Combebias A, Fadel R. Quality of life and symptoms assessment in sublingual immunotherapy for patients with house-dust mite related perennial rhinitis: denition of a responder prole. World Allergy Organization Journal. XXth World Allergy Organization Congress & VIIth Asia Pacic Congress of Allergology, 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 pollen allergic patients: a double blind (double dummy) study. Clinical and Experimental Allergy 1996;26(11):125361. Radu 2007 {published data only} Radu J, Du Buske L. Clinical efcacy and side effects of sublingual immunotherapy vs. placebo in children with perennial allergic rhinitis and asthma, sensitised to house dust 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-month treatment with grass tablets in 259 patients with grass pollen rhinoconjuntivitis. Allergy 2009;64 Suppl 90:146. Roberta 2009b {published data only} Roberta A, Milani M, Pecora S. Safety, tolerability and efcacy of a grass tablet 12-month treatment: a prospective multicenter trial in 259 patients with grass pollen rhinoconjuntivitis. Allergy 2009;64 Suppl 90:464. Rossi 2005 {published data only} Rossi RE, Monasterolo G. A pilot study of feasibility of ultrarush (20-25 minutes) sublingual-swallow immunotherapy in 679 patients (699 sessions) with allergic rhinitis and/ or asthma. International Journal of Immunopathology and Pharmacology 2005;18(2):27785. Rukhadze 2008 {published data only} Rukhadze M, Dolidze N, Abramidze T, Lomidze N, Gotua M, Gamkrelidze A. Allergen-specic immunotherapy in Georgia. Allergy 2008;63 Suppl 88:529.
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Sabbah 1994 {published data only} Sabbah A, Hassoun S, Le Sellin J, Andr C, Sicard H. A double-blind, placebo-controlled trial by the sublingual route of immunotherapy with a standardized grass pollen extract. Allergy 1994;49(5):30913. Scadding 1986 {published data only} Scadding GK, Brostoff J. Low dose sublingual therapy in patients with allergic rhinitis due to house dust mite. Clinical Allergy 1986;16(5):48391. Sieber 2009 {published data only} Sieber J, Shah-Hosseini K, Moesges R. Grass pollen sit in daily medical practice - effectiveness of sublingual immunotherapy is comparable with subcutaneous treatment. Allergy 2009;64 Suppl 90:347. Stelmach 2009 {published data only} Stelmach I, Kaczmarek-Wozniak J, Majak P, OlszowiecChlebna M, Jerzynska J. Efcacy and safety of high-doses sublingual immunotherapy in ultra-rush scheme in children allergic to grass pollen. Clinical and Experimental Allergy 2009;39(3):4018. Stosovic 2008 {published data only} Stosovic R, Bogic M, Tomic Spiric V. Long-term efcacy and safety of sublingual immunotherapy in seasonal allergic rhinitis. Allergy 2008;63 Suppl 88:392. Tari 1990 {published data only} Tari MG, Mancino M, Monti G. Efcacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite. A double-blind study. Allergologia et Immunopathologia 1990;18(5):27784. Tonnel 2004 {published data only} Tonnel AB, Scherpereel A, Douay B, Mellin B, Leprince D, Goldstein N, Delecluse P, Andre C. Allergic rhinitis due to house dust mites: evaluation of the efcacy of specic sublingual immunotherapy. Allergy 2004;59(5):4917. Troise 2009 {published data only} Troise C, Voltolini S, Incorvaia C, La Grutta S, Bignardi D, Frati F. Efcacy and safety of sublingual immunotherapy with 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 specic IgG4 and IgG4/ IgE ratio in mite-sensitized Taiwanese children with allergic rhinitis receiving short-term sublingual-swallow immunotherapy: a multicenter, randomized, placebo-controlled trial. Asian Pacic Journal of Allergy and Immunology 2008;26(2-3): 10512. Ventura 2009 {published data only} Ventura MT, Carretta A, Tummolo RA, Buquicchio R, Arsieni A, Murgia N. Clinical data and inammation parameters in patients with cypress allergy treated with sublingual swallow therapy and subcutaneous immunotherapy. International Journal of Immunopathology and Pharmacology 2009;22(2):40313.
Wessner 2001 {unpublished data only} Wessner DB, Wessner S, Mohrenschlager M, Rakoski J, Ring J. Efcacy and safety of sublingual immunotherapy in adults with allergic rhinoconjunctivitis: results after 2 years of a controlled trial. Allergy 2001;56 Suppl 68:88. Worm 2006 {published data only (unpublished sought but not used)} Worm M. Efcacy and tolerability of high dose sublingual immunotherapy in patients with rhinoconjunctivitis. European Annals of Allergy and Clinical Immunology 2006; 38(10):35560. Worm 2009 {published data only} Worm M. Well Days after sublingual immunotherapy with a high-dose 6-grass pollen preparation. Allergy 2009;64(7): 11045. Yuksel 1999 {published data only} Yuksel H, Tanac R, Gousseinov A, Demir E. Sublingual immunotherapy and inuence on urinary leukotrienes in seasonal pediatric allergy. Journal of Investigational Allergology and Clinical Immunology 1999;9(5):30513.
Additional references
Abramson 2003 Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database of Systematic Reviews 2003, Issue 4. [DOI: 10.1002/ 14651858.CD001186] Baroody 2009 Baroody FM, Shenaq D, DeTineo M, Wang J, Naclerio RM. Fluticasone furoate nasal spray reduces the nasal-ocular reex: a mechanism for the efcacy of topical steroids in controlling allergic eye symptoms. Journal of Allergy and Clinical Immunology 2009;123(6):13428. Begg 1994 Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50(4): 1088101. Berger 2005 Berger W, Abelson MB, Gomes PJ, Beck M, Kimura S, Westbrook T, et al.Effects of adjuvant therapy with 0.1% olopatadine hydrochloride ophthalmic solution on quality of life in patients with allergic rhinitis using systemic or nasal therapy. Annals of Allergy, Asthma & Immunology 2005;95(4):3617. Bielory 2002 Bielory L, Mongia A. Current opinion of immunotherapy for ocular allergy. Current Opinion in Allergy and Clinical Immunology 2002;2(5):44752. Bielory 2007a Bielory L. Differential diagnoses of conjunctivitis for clinical allergist-immunologists. Annals of Allergy, Asthma & Immunology 2007;98(2):10514. Bielory 2007b Bielory L, Katelaris CH, Lightman S, Naclerio RM. Treating the ocular component of allergic rhinoconjunctivitis and related eye disorders. MedGenMed 2007;9(3):35.
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Bielory 2008a Bielory L. Ocular allergy overview. Immunology & Allergy Clinics of North America 2008;28(1):123. Bielory 2008b Bielory L. Ocular symptom reduction in patients with seasonal allergic rhinitis treated with the intranasal corticosteroid mometasone furoate. Annals of Allergy, Asthma & Immunology 2008;100(3):2729. Bohle 2007 Bohle B, Kinaciyan T, Gerstmayr M, Radakovics A, JahnSchmid B, Ebner C. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specic Tcell tolerance, and immune deviation. Journal of Allergy & Clinical Immunology 2007;120(3):70713. Buckley 1998 Buckley RJ. Allergic eye disease - a clinical challenge. Clinical and Experimental Allergy 1998;28 Suppl 6:3943. Calderon 2007 Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham SR. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database of Systematic Reviews 2007, Issue 1. [DOI: 10.1002/14651858.CD001936] Calderon 2008 Caldern MA, Penagos M, Durham SR. Sublingual immunotherapy for allergic rhinoconjunctivitis, allergic asthma, and prevention of allergic diseases. Clinical Allergy and Immunology 2008;21:35975. Canonica 2007 Canonica GW, Bousquet J, Mullol J, Scadding GK, Virchow JC. A survey of the burden of allergic rhinitis in Europe. Allergy 2007;62 Suppl 85:1725. Canonica 2008 Canonica GW, Fumagalli F, Guerra L, Baiardini I, Compalati E, Rogkakou A, et al. Global Allergy and Asthma European Network. Levocetirizine in persistent allergic rhinitis: continuous or on-demand use? A pilot study. Current Medical Research and Opinion 2008;24(10): 282939. Cochrane open learning material 2002 Alderson P, Green S. Meta-analysis of continuous data. Cochrane Collaboration open learning material for reviewers 2002:A1. Dahl 2007 Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, Emminger W, et al.Sublingual grass allergen tablet immunotherapy provides sustained clinical benet with progressive immunologic changes over 2 years. Journal of Allergy and Clinical Immunology 2008;121(2):5128. Dawson 2004 Dawson B, Trapp RG. Research questions about one group. Basic & clinical biostatistics. 4th Edition. New York: McGraw-Hill Professional, 2004:118. Deeks 2011 Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 9: Analysing data and undertaking meta-analyses. In: Higgins
JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Dolz 1996 Dolz I, Martnez-Ccera C, Bartolom JM, Cimarra M. A double-blind, placebo-controlled study of immunotherapy with grass-pollen extract Alutard SQ during a 3-year period with initial rush immunotherapy. Allergy 1996;51(7): 489500. Durham 2007a Durham SR, Riis B. Grass allergen tablet immunotherapy relieves individual seasonal eye and nasal symptoms, including nasal blockage. Allergy 2007;62(8):9547. Durham 2007b Durham SR. Tradition and innovation: nding the right balance. Journal of Allergy and Clinical Immunology 2007; 119(4):7925. Durham 2008 Durham SR. Sublingual immunotherapy: what have we learnt from the big trials?. Current Opinion in Allergy and Clinical Immunology 2008;8(6):57784. Egger 1997 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109):62934. Frew 2006 Frew AJ, Powell RJ, Corrigan CJ, Durham SR. UK Immunotherapy Study Group. Efcacy and safety of specic immunotherapy with SQ allergen extract in treatmentresistant seasonal allergic rhinoconjunctivitis. Journal of Allergy and Clinical Immunology 2006;117(2):31925. Glanville 2006 Glanville JM, Lefebvre C, Miles JN, Camosso-Stenovic J. How to identify randomized controlled trials in MEDLINE: ten years on. Journal of the Medical Library Association 2006; 94(2):1306. Higgins 2002 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002;21(11):153958. Higgins 2003 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414):55760. Higgins 2011a Higgins JPT, Deeks JJ (editors). Chapter 7: Selecting studies and collecting data. In: Higgins JPT, Green S, editors, Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Higgins 2011b Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins
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JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Jackson 1991 Jackson WB. Differentiating conjunctivitis of diverse origins. Survey of Ophthalmology 1993;38 Suppl:91104. Moingeon 2006 Moingeon P, Batard T, Fadel R, Frati F, Sieber J, Van Overtvelt L. Immune mechanisms of allergen-specic sublingual immunotherapy. Allergy 2006;61(2):15165. Mortemousque 2003 Mortemousque B, Bertel F, De Casamayor J, Verin P, Colin J. House-dust mite sublingual-swallow immunotherapy in perennial conjunctivitis: a double-blind, placebo-controlled study. Clinical and Experimental Allergy 2003;33(4):4649. Murdoch 1998 Murdoch IE, Morris SS, Cousens SN. People and eyes: statistical approaches in ophthalmology. British Journal of Ophthalmology 1998;82(8):9713. Patrick 2008 Patrick D, Guyatt GH, Acquadro C. Chapter 17: Patient-reported outcomes. In: Higgins JPT, Green S, editors, Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Penagos 2006 Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Huerta J, Passalacqua G, et al.Efcacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Annals of Allergy, Asthma & Immunology 2006;97(2):1418. Penagos 2008 Penagos M, Passalacqua G, Compalati E, Baena-Cagnani CE, Orozco S, Pedroza A, et al.Metaanalysis of the efcacy of sublingual immunotherapy in the treatment of allergic asthma in pediatric patients, 3 to 18 years of age. Chest 2008;133(3):599609. Radulovic 2007b Radulovic S, Calderon MA, Wilson DR, Durham SR. Cochrane systematic review: Safety prole of sublingual
immunotherapy (SLIT) for allergic rhinitis (AR). Journal of Allergy and Clinical Immunology 2008;121 Suppl 1(2):142. Radulovic 2010 Radulovic S, Calderon M, Wilson S, Durham SR. Sublingual immunotherapy for allergic rhinitis. Cochrane Database of Systematic Reviews 2011, Issue 2. [DOI: 10.1002/14651858.CD002893.pub2] RevMan 2011 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011. Scadding 2008 Scadding GK, Keith PK. Fluticasone furoate nasal spray consistently and signicantly improves both the nasal and ocular symptoms of seasonal allergic rhinitis: a review of the clinical data. Expert Opinion in Pharmacotherapy 2008;9 (15):270715. Scadding 2009 Scadding G, Durham SR. Mechanisms of sublingual immunotherapy. Journal of Asthma 2009;46(4):32234. Singh 2010 Singh K, Axelrod S, Bielory L. The epidemiology of ocular and nasal allergy in the United States, 1998-1994. Journal of Allergy and Clinical Immunology 2010;126(4):77883. Sterne 2001 Sterne JA, Egger M, Smith GD. Systematic reviews in health care: Investigating and dealing with publication and other biases in meta-analysis. BMJ 2001;323(7304):1015. Sutton 2008 Sutton AJ, Higgins JP. Recent developments in metaanalysis. Statistics in Medicine 2008;27(5):62550. Torkildsen 2009 Torkildsen GL, Gomes P, Welch D, Gopalan G, Srinivasan S. Evaluation of desloratadine on conjunctival allergen challenge-induced ocular symptoms. Clinical and Experimental Allergy 2009;39(7):10529. Wilson 2005 Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy 2005;60(1):412. Indicates the major publication for the study
28
CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID]

Andre 2003 Methods Study design: Randomised, parallel-group, double-masked and placebo controlled clinical trial Country: France Setting: Specialist care Number randomised: 110 participants Age: Children and adults Gender: Female 59% (n = 65) Inclusion criteria: Age between 7 and 55 years, an allergy to ragweed pollen as assessed by a clinical history (seasonal allergic rhinitis), positive skin-prick tests and specic IgE (positive RAST class II and above). Exclusion criteria: Patients with symptomatic polysensitisations, asthma not controlled by beta 2-agonists, current treatment with long-acting antihistamine agents, beta-blocking agents (even topical), inhaled or oral corticosteroids, cromones. SLIT: Standardised ragweed extract. Solution and then tablets. Placebo: Solution and then tablets with an appearance similar to that of the active agent. Total ocular symptom scores Individual ocular symptom scores (grittiness, redness, itching, watery eyes) Ocular medication scores Allergen: Ragweed Participants numbers for total and individual ocular symptom scores were 26 for active and 48 for placebo groups (Table 4, p 166), whilst for ocular medications were 44 participants 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 3 times a week). Potential conicts of interest: First author works with Stallergnes, Antony, France
Participants
Interventions
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. Not stated in paper. Investigators and participants were masked to treatment assignment for the duration of the study.
Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Unclear risk
Blinding (performance bias and detection Low risk bias) All outcomes
29
Andre 2003
(Continued)
Incomplete outcome data (attrition bias) All outcomes
Low risk
Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Selective reporting (reporting bias)
Low risk
Other bias
Low risk
Ariano 2001 Methods Study design: Randomised, parallel-group, double-masked and placebo controlled clinical trial Country: Italy Setting: Specialist care Number randomised: 20 participants Age: Adults Gender: Female 55% (n = 11) Inclusion criteria: Rhinoconjunctivitis and/or mild asthma associated with Cupressaceae pollen, positive skin tests, positive RAST, positive nasal provocation test. Exclusion criteria: Not described. SLIT: The active traitment consisted in an aqueous solution of an allergic fraction of Cupressus arizonica partially puried through dialysis in a physiological solution with 15 % glycerin. As previously stated, the extract was standardised according to the following associated methods: RAST inhibition and Histamine equivalency. The titration was carried out in RAST UNIT/ml. The participants were instructed to keep the liquid for at least 2 minutes under the tongue before swallowing it (SLIT-SWALLOW technique). Treatment model: there was 5 vials with the following concentrations (vial n. 1: 100 U RAST/ml; vial n. 2: 300 U RAST/ml; vial n. 3: 1,000 U RAST/ml; vial n. 4: 4,000 U RAST/ml; vial n. 5: 10,000 U RAST/ml). The initial phase which lasted 50 days consisted in taking 5 drops every day from vial 1 to vial 5. During the maintenance treatment which lasted 6 months, participants had to take drops of vial 5 every other day. The total average cumulative dosis was 250,000 U RAST for each patient which is 5 times more than the usual dosage in classical subcutaneous immunotherapy. Placebo: No details provided. Total ocular symptom scores Allergen: Cupressus arizonica Potential conicts of interest: Anallergo s.r.l. Firenze, Italy
Participants
Interventions
Outcomes Notes
Risk of bias Bias Authors judgement Support for judgement
30
Ariano 2001
(Continued)
Participants were randomised but how this was done was not stated. Not stated in paper. Investigators and participants were masked to treatment assignment for the duration of the study. All participants completed the study.
Blinding (performance bias and detection Low risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Low risk
Low risk
The specied outcomes in the methodology were reported in the results section. Insufcient information to assess whether an important risk of bias exists.
Other bias
Unclear risk
Aydogan 2007 Methods Study design: Randomised, parallel-group, double-masked and placebo controlled clinical trial Country: Turkey Setting: Specialist care Number randomised: 18 participants Age: Children Gender: Male 11 and female 4 (per protocol population) Inclusion criteria: Children with diagnosis of allergic rhinitis sensitised to house dust mites. Exclusion criteria: No details provided. SLIT: Standardised 300 IR D. Pteronyssinus + D. farinae 50/50 % extract for a period of 1 year. Placebo: No details provided. Total ocular symptom scores Individual ocular symptom scores (redness, itching, watery eyes) Allergen: Mites Abstract from meeting Potential conicts of interest: No data available
Participants
Interventions
Outcomes
Notes
31
Aydogan 2007
(Continued)
Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Unclear risk
Random number table used.
Not stated in paper. Investigators and participants were masked to treatment but how this was done was not stated. No details were provided.
Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Other bias Unclear risk
Unclear risk Unclear risk
Outcomes were described in abstract Insufcient information to assess whether an important risk of bias exists.
Bowen 2004 Methods Study design: Randomised, parallel-group, double-masked and placebo controlled clinical trial, multicentre Country: Canada Setting: Specialist care (9 allergy centres) Number randomised: 83 participants Age: Children and adults Gender: ITT population: Male 45 (59%) and female 31 (41%) Inclusion criteria: Patients of either sex, aged 6 to 58 years, with a history of previous seasonal allergic rhinoconjunctivitis during the ragweed pollen season and positive skin prick test reactions to ragweed (3 mm > than the negative control). Exclusion criteria: Symptomatic polysensitisation; asthma not controlled with beta-agonist therapy; current therapy with inhaled or oral corticosteroids, beta-blocking agents, long-acting antihistamine agents, or cromones; and previous immunotherapy. SLIT: Standardised ragweed allergen extract (Ambrosia eliator). During a 17-day dose progression phase, the participants received a daily dose of 0.5 to 300 IR. Treatment was maintained at the highest tolerated dose (minimum: 100 IR and 116 g Amb a 1; maximum: 20 drops daily, 1 mL, 300 IR/mL, and 314 g of Amb a 1) during a maintenance phase (pollen season). Placebo: No details provided. Total ocular symptom scores Individual ocular symptom scores (grittiness, redness, itching, watery eyes) Allergen: Ambrosia eliator Potential conicts of interest: Funded by Stallergnes
Participants
Interventions
Outcomes
Notes
Risk of bias
Bowen 2004
(Continued)
Bias
Authors judgement
Support for judgement Participants were randomised but how this was done was not stated. Not stated in paper. Investigators and participants were masked to treatment but how this was done was not stated. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Low risk
Low risk
Other bias
Low risk
Bufe 2004 Methods Study design: Randomised, parallel-group, double-masked and placebo controlled clinical trial, multicentre Country: Germany Setting: Specialist care (33 paediatricians organised in the NETSTAP e.V.) Number randomised: 161 participants Age: Children Gender: No details were provided Inclusion criteria: Participants were selected according to a history of summer hay fever. Inclusion criteria were doctors diagnosis of rhinoconjunctivitis, allergic asthma or both and positive-SPT towards grass pollen allergen extract. Symptoms had to be restricted to the grass pollen season from May to September. Exclusion criteria: Participants with parallel SPT reactivities to 3 or more other allergen groups (i.e. animal dander, mites, and moulds), with chronic asthma, with previous immunotherapy or other systemic diseases such as diabetes, leukaemia or immunodeciency. 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 phase participants received 2500 AU every day. After 3 years participants had ingested a mean of 5250 allergen drops (2.625.000 AU). This was equivalent to a cumulative dosage of 9.6 mg major allergen Phl p 5 (timothy grass pollen, data given by HAL-Allergy). Placebo: Placebo containing the solvent used for the treatment extract.
Participants
Interventions
33
Bufe 2004
(Continued)
Outcomes Notes
Combined ocular symptom and medication scores Allergen: Mix grass Potential conicts of interest: HAL-Allergy Group
Risk of bias Bias Authors judgement Support for judgement Blockwise randomisation was performed.
Not stated in paper. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Blinding (performance bias and detection Low risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Low risk
Low risk
Other bias
Low risk
Bufe 2008 Methods Study design: Randomised, parallel-group, double-masked and placebo controlled clinical trial, multicentre Country: Germany Setting: Specialist care (26 paediatricians organised in the NETSTAP e.V.) Number randomised: 253 participants Age: Children Gender: Male 66% (n = 166) Inclusion criteria: 5 to 16 years of age; at least 1 year clinical history of grass polleninduced allergic rhinoconjunctivitis having received symptomatic treatment during the previous grass pollen season; positive skin prick test against P pratense, wheal diameter > 3 mm; specic IgE against P pratense, IgE class 2. Exclusion criteria: clinical history of chronic sinusitis or perennial or seasonal allergic rhinitis and/or asthma because of another allergen during-or potentially overlapping-the grass pollen season; severe asthma; previous treatment by allergen-specic immunotherapy within the previous 5 years or pregnancy.
Participants
34
Bufe 2008
(Continued)
Interventions
SLIT: Orodispersible, fast-dissolving, SQ-standardised grass allergen tablet (75,000 SQT/2800 bioequivalent allergen units, approximately 15 mg Phl p 5, Phleum pratense major allergen 5). The treatment was commenced a minimum of 8 weeks before the start of the grass pollen season. Placebo: Placebo tablet similar in taste, smell, and appearance. Total ocular symptom scores Allergen: Phleum pratense Potential conicts of interest: ALK-Abell
Outcomes Notes
Risk of bias Bias Authors judgement Support for judgement Randomisation was performed by stratication according to trial centre. Not stated in paper. Investigators and participants were masked to treatment assignment for the duration of the study. Reported in paper.
Low risk
The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Other bias
Low risk
Cao 2007 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: China Setting: Specialist care Number randomised: 278 participants Age: Children Gender: Male 174 and female 104 Inclusion criteria: Participants aged 4 to 18 years old had to have mild or moderate allergic asthma, allergic rhinitis or both. Skin prick test positive to HDM. Exclusion criteria: Participants were excluded if any evidence of renal, hepatic, cardiac or pulmonary diseases other than asthma was found. Those participants in other drug trials 4 weeks before the inclusion to this study.
35
Cao 2007
(Continued)
Interventions
SLIT: Treatments were given as daily drops for 25 weeks. Participants were given at the following doses: 1st week: Vial 1. Drops with concentration at 1g/ml, daily: Mon 1 drop, Tue 2 drops, Wed 3, Thu 4, Fri 6, Sat 8 and Sun 10 drops. 2nd week: Vial 2. Drops with concentration at 10g/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 g/ ml, daily: Mon 1 drop, Tue 2 drops, Wed 3, Thu 4, Fri 6, Sat 8 and Sun 10 drops. 4th to 25th week: Vial 4: Drops with concentration at 333 g/ml, daily, 3 drops: 1 drop = 40 L. Placebo: Placebo was a solution with glycerosaline and it matched with the active treatment in presentation, quantity, avour and package. Total ocular symptom scores Individual ocular symptom scores (grittiness, redness, itching, watery eyes) Ocular medication scores Allergen: Mites This trial included 40 pairs of patients with allergic asthma, 32 pairs with allergic rhinoconjunctivitis and 67 with both. Potential conicts of interest: No data available
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. Not stated in paper. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Low risk
Other bias
Low risk
36
Casanovas 1994 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Spain Setting: Specialist care Number randomised: 15 participants Age: Adults Gender: 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 tests positive to Olea pollen and high levels of specic IgE to Olea pollen. Exclusion criteria: Sensitisation to other common aeroallergens and previous immunotherapy. SLIT: Aqueous extract of the pollen of O. europaea standardised on a w/v basis. Treatment was preseasonal. Placebo: Glycerinated phenol saline solution. Total ocular symptom scores Allergen: Olea europaea Potential conicts of interest: CBF-LETI, S.A. Madrid
Interventions
Outcomes Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. Not stated in paper. Investigators and participants were masked to treatment assignment for the duration of the study. Participants excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. Insufcient information to assess whether an important risk of bias exists. Small number of participants across each trial group.
Low risk
Other bias
Unclear risk
37
Dahl 2006a Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: Austria, Denmark, Germany, Italy, The Netherlands, Spain, Sweden, and United Kingdom Setting: 51 specialist care centres in 8 countries Number randomised: 634 participants Age: Adults Gender: Male 59% (n = 372) Inclusion criteria: 18 to 65 years old; at least 2-year clinical history of signicant grass pollen-induced allergic rhinoconjunctivitis; specic IgE against Phleum pratense CAP class 2; positive skin prick test against Phleum pratense, wheal diameter 3 mm; and FEV1 higher than 70% of predicted value. Exclusion criteria: Signicant asthma outside the grass pollen season; FEV1 lower than 70% of predicted value; allergic rhinitis requiring medication caused by allergens other than grass during the treatment period (participants with positive skin tests to other allergens in the absence of symptoms were permitted); conjunctivitis, rhinitis, or asthma at the screening or randomisation visits; history of anaphylaxis; immunosuppressive treatment; receipt of immunotherapy with grass pollen allergen within the previous 10 years or any other allergen within the previous 5 years; and pregnancy. SLIT: Orodispersible grass allergen tablet 75,000 SQ-T (GRAZAX; approximately 15 g major allergen Phleum p 5). The treatment started 16 weeks before the expected start 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 followup. Results from the rst treatment season are presented here. Placebo: Tablet similar in taste, smell, and appearance once daily. Total ocular symptom scores Individual ocular symptom scores (grittiness, redness, itching, watery eyes) Allergen: Phleum pratense Potential conicts of interest: Funded by ALK-Abell
Participants
Interventions
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement The allocation sequence was generated by the sponsoring company and masked for the investigators. Central allocation. Investigators and participants were masked to treatment assignment for the duration of the study.
Random sequence generation (selection Low risk bias)
Allocation concealment (selection bias)
Low risk
38
Dahl 2006a
(Continued)
Low risk
Participants excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Low risk
Other bias
Low risk
Dahl 2006b Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: Denmark and Sweden Setting: 15 specialist care centres (11 in Denmark and 4 in Sweden) Number randomised: 114 participants Age: Adults Gender: Male 68% (n = 77) Inclusion criteria: Age 18 to 65; clinical history of signicant grass pollen-induced allergic rhinoconjunctivitis and mild to moderate grass pollen-induced asthma of 2 years or more; well controlled seasonal asthma in accordance with the GINA Guideline; a positive skin prick test (wheal diameter 3 mm) and specic immunoglobulin E (IgE; CAP allergy class 2) to P. pratense. Exclusion criteria: Signicant asthma outside the grass pollen season; FEV1 < 70% of predicted value; signicant allergic rhinitis (requiring medication) caused by allergens other than grass during the planned treatment period; conjunctivitis, rhinitis or asthma at the screening or randomisation visits; history of anaphylaxis; immunosuppressive treatment; hypersensitivity to the excipients of the trial medication or rescue medication; having received immunotherapy with grass pollen allergen within the previous 10 years or any other allergen within the previous 5 years; pregnancy. SLIT: Orodispersible grass allergen tablet 75,000 SQ-T (GRAZAX; approximately 15 g major allergen Phleum p 5). Trial was given 10-14 weeks prior to and during the grass pollen season 2004. Placebo: Tablet similar in taste, smell, and appearance once daily. Total ocular symptom scores Individual ocular symptom scores (grittiness, redness, itching, watery eyes) Ocular medication scores Allergen: Phleum pratense Potential conicts of interest: Supported by ALK-Abell
Participants
Interventions
Outcomes
Notes

39
Dahl 2006b
(Continued)
The allocation sequence was generated by the sponsoring company and masked for the investigators. Central allocation. Unmasked efcacy and safety assessments on subject level were available only for a biostatistician at the Contract Research Organization. All personnel associated with the study and participants remained masked. Reported in paper.
Low risk
Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias)
Low risk
Low risk
Other bias
Low risk
de Blay 2007 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: France Setting: 15 specialist care centres Number randomised: 118 participants Age: Children and adults Gender: ITT population: Male 69 (66%) and female 35 (34%) Inclusion criteria: Seasonal allergic rhinoconjunctivitis for at least the past 2 years, with or without intermittent asthma (FEV1 80% of the predicted value on enrolment into the study); (2) sensitisation to grass pollen with positive skin prick test results with a 3 grass pollen extract (Dactylis, Phleum, or Lolium); and (3) specic IgE anti-Dactylis antibodies (class 2 or higher) (CAP System; Pharmacia, Uppsala, Sweden). Exclusion criteria: Sensitisation to perennial allergens or to animal allergens if the animal was present in the patients immediate environment, sensitisation to weed and tree pollen with clinical manifestations, immune diseases, and previous specic immunotherapy for grass pollen. Use of drugs that might interfere with evaluation of the clinical scores. 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 of 5 weeks, they reached the maintenance dose, a 300 IR 3 grass pollen extract 3 times a week. By the end of the study, each patient in the active treatment group had received a
40
Participants
Interventions
de Blay 2007
(Continued)
mean cumulative dose of 31,800 IR of the 3 grass pollen extract, corresponding to 2.75 mg of group 5 grass pollen major allergen. Placebo: Placebo (phenol-free saline solution in 50% glycerin). Outcomes Total ocular symptom scores Individual ocular symptom scores (red, itchy, watery eyes) Ocular medication scores Allergen: Grass mix Potential conicts of interest: Supported by Allerbio Laboratory
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but it is not stated in the paper how it was done. Not stated in paper. Investigators and participants were masked to treatment assignment for the duration of the study. Reported in paper.
Low risk
Other bias
Low risk
Didier 2007 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: Austria, Bulgaria, Czech Republic, Denmark, France, Germany, Hungary, Italy, Slovakia and Spain Setting: 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 participants Age: Adults Gender: 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
41
Participants
Didier 2007
(Continued)
grass pollen-related allergic rhinoconjunctivitis for at least 2 years, conrmed by a positive skin prick test (wheal size to 3 mm) and serum specic IgE of at least class 2 (CAP System; Phadia, Uppsala, Sweden) to grass pollen assessed at the screening visit. The skin prick 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 10 most common allergens in each country. Participants sensitised to allergens other than grass pollen were included as well as those with asthma requiring treatment only with beta 2-agonists. Exclusion criteria: The main exclusion criteria were allergic rhinoconjunctivitis caused by a co-sensitisation likely to inuence symptoms of the patient throughout the study or symptoms of rhinoconjunctivitis during the treatment phase because of sensitisation to allergens other than grass pollens, previous specic immunotherapy (SIT) for grass pollen, 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 were given 1 of 3 daily doses (100 IR, 300 IR, or 500 IR) of the SLIT tablets. The mean dosage of 300 IR/mL corresponded to approximately 25 mg/mL of the group 5 major allergens. In November 2004, approximately 5 months before the expected start of the pollen season, participants were screened for eligibility and randomised 1:1:1:1 to 1 of the 4 treatment groups (100 IR, 300 IR, 500 IR, or placebo). During the rst 5 days of treatment, doses were increased by 100 IR until the nal dose was achieved. The 300 IR dose demonstrated a signicant efcacy compared with placebo, therefore this dose was chosen by the authors as a therapeutic dose for clinical practice. Placebo: The placebo tablet matched the active treatment in size, shape, and colour but contained no pollen allergens or other active ingredients. Total ocular symptom scores Individual ocular symptom scores (grittiness, redness, itching, watery eyes) Allergen: Grass mix Potential conicts of interest: Supported by Stallergnes
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement Computer-generated randomisation list utilised. Central allocation. Both investigators and participants were masked to allocation. To maintain the masking, participants took 2 tablets per day during the rst 5 days of titration and 1 tablet per day from day 6 until the end of
42
Random sequence generation (selection Low risk bias) Allocation concealment (selection bias) Low risk
Didier 2007
(Continued)
treatment. Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Low risk Reported in paper.
Low risk
Other bias
Low risk
Dubakiene 2003 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: The Netherlands Setting: Specialist care Number randomised: 119 participants Age: Children and adults Gender: Female 54% Inclusion criteria: Participants with allergic complaints, positive SPT for trees (wheal > 4 mm) and positive IgE trees. Exclusion criteria: Data not available. SLIT: Combination birch / alder / hasel. 5 drops/day = 0.25 mL, cumulative dose is 30 mL. Mean treatment duration 4 months. Placebo: Not described Total ocular symptom scores Individual ocular symptom scores (grittiness, redness, itching, watery eyes) Ocular medication scores Allergen: Tree pollen Potential conicts of interest: HAL-Allergy
Interventions
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement Randomisation in blocks of 4 was performed (2 SLIT and 2 placebo). Not reported. Investigators and participants were masked to treatment but how this was done was not stated in the paper.
Blinding (performance bias and detection Unclear risk bias) All outcomes
43
Dubakiene 2003
(Continued)
Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Other bias
Low risk
Participants lost to follow-up or excluded were analysed. It is not reported in the abstract. This paper has not been published.
Unclear risk Unclear risk
Durham 2006 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: Belgium, Denmark, Germany, Sweden, Austria, Norway, the United Kingdom and Canada Setting: 55 specialist care centres in centres in Europe and Canada Number randomised: 855 participants Age: Adults Gender: Male 62% (n = 533) Inclusion criteria: 18 to 65 years of age who gave a clinical history of troublesome symptoms of allergic rhinoconjunctivitis during the grass pollen season of a duration of at least 2 years, a positive skin prick test to P pratense (wheal diameter 3 mm), raised serum allergen-specic IgE to P pratense, and no signicantly abnormal ndings on physical examination. Exclusion criteria: Clinical history of signicant asthma outside the grass pollen season; FEV1 < 70% of the predicted value; signicant allergic rhinitis (requiring medication) caused by allergens other than grass during the planned treatment period; signicant recurrent acute sinusitis or chronic sinusitis; conjunctivitis, rhinitis, or asthma at the screening or randomisation visits; a history of anaphylaxis or angioedema; presence of serious underlying conditions; immunosuppressive treatment; hypersensitivity to excipients of trial medications or rescue medications; or having received immunotherapy with grass pollen allergen within the previous 10 years or any other allergen within the previous 5 years. Pregnant women and those at risk of pregnancy were also excluded. SLIT: Active treatment involved an orodispersible, fast-dissolving grass allergen tablet (ALK-Abell A/S) containing a standardised grass allergen extract from timothy grass (P pratense). Participants received 2500, 25,000 or 75,000 SQ-T. Respectively, this corresponded 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. Total ocular symptom scores Individual ocular symptom scores (grittiness, redness, itching, watery eyes) Allergen: Phleum pratense Potential conicts of interest: Supported by ALK-Abell
Participants
Interventions
Outcomes
Notes
Risk of bias
44
Durham 2006
(Continued)
Bias
Authors judgement
Support for judgement The allocation sequence was generated by the sponsoring company and masked for the investigators (computer-generated schedule). Central allocation. Investigators and participants were masked to treatment assignment for the duration of the study. Tablet similar in taste, smell, and appearance. Reported in paper.
Low risk
Low risk
Low risk
Other bias
Low risk
Feliziani 1995 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Italy Setting: 2 specialist care centres (Parma and Lanciano) Number randomised: 34 participants Age: 14 to 48 years old (Inclusion criteria) Gender: Not specied Inclusion criteria: Sensitisation only to grass pollen proved by means of skin prick test and/or RAST; at least 2 years of oculo-rhinitis with or without asthma, clearly related to the grass pollen season. Exclusion criteria: Severe asthma, nasal polyps, pregnancy, continuous treatment with steroids, chronic diseases of the airways, auto-immune diseases, specic immunotherapy in progress or interrupted 5 years before to this study, no compliance. 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 glycerol and 0.4% W/V of phenol as preservative in physiological saline. A schedule of rush pre-seasonal treatment was followed, with drops to be taken sublingually twice a day between meals, starting from 1 drop (0.04 BU/mL) up to 5 drops of the same vial and then repeating the same procedure up to 5 drops of the 100 BU/mL or the maximum lower dose well tolerated. A co-seasonal maintenance treatment then followed with the top 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.
45
Interventions
Feliziani 1995
(Continued)
Placebo: Identical solution prepared in identical vials with the same appearance, colour, taste but without the allergens. Outcomes Total ocular symptom scores Individual ocular symptom scores (red and itchy eyes) Allergen: Grass mix Potential conicts of interest: Neo-Abell
Notes
Risk of bias Bias Authors judgement Support for judgement Treatments were coded according to a key unknown to the clinician and to the patient and they were assigned randomly to each patient. This is not reported in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. Insufcient information to assess whether an important risk of bias exists.
Unclear risk
Low risk
Other bias
Unclear risk
Hirsch 1997 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Germany Setting: Specialist care Number randomised: 30 participants Age: Children Gender: Male 20 and female 10 Inclusion criteria: Clinical history of allergic asthma, allergic rhinitis or both. All participants were allergic to Dermatophagoides pteronyssinus (D.pt.) documented by positive skin prick test, specic IgE (D.pt.) of > Class 2 (Pharmacia CAP), 3. positive nasal provocation response to D.pt. (> 40% ow reduction or 60% increase of nasal resistance to 8000 SBU/ml resp. 4.2 pg/ml Der p 1).
46
Hirsch 1997
(Continued)
Exclusion criteria: Previous immunotherapy with D.pt., use of oral steroids, or any other signicant illness. Interventions SLIT: Active treatment involved a puried whole mite hody extract in 50% aqueous glycerol (Allergopharma J. Ganzer KG, Reinhek, FRG) over 12 months. In a 3-week build-up phase participants took daily increasing doses from 1 to 7 drops of a 1:100 dilution of the nal preparation in the rst week, 1 to 7 drops of a 1:10 dilution in the second week, and 1 to 7 drops of the nal preparation in the third week. Maintenance was given as 7 drops on 3 days per week. The Der p I content of the active preparation was 11.9 g/ml, so 1 drop (= 0.045 ml) contained 0.535 g. The cumulative dose Der p I in 12 months was estimated to be approximately 570 g. Placebo: Vehicle alone. Total ocular symptom scores Allergen: Mites Potential conicts of interest: Not declared
Outcomes Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised according to a code provided by the manufacturer. Central allocation. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. Insufcient information to assess whether an important risk of bias exists.
Low risk
Other bias
Unclear risk
Horak 1998 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Austria Setting: Specialist care centre Number randomised: 41 participants
47
Horak 1998
(Continued)
Age: Adults Gender: Male 15 and female 26 Inclusion criteria: Participants suffering from seasonal allergic rhinoconjunctivitis of at least 2 years of duration, positive skin prick test to Betula alba extract, positive conjunctival 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 specic IgE to betula alba by the RAST method were included. Exclusion criteria: Participants who received specic immunotherapy during the last 2 years, pregnant and nursing women and participants with contraindications to immunotherapy were excluded. Interventions SLIT: Treatment consisted in a biologically standardised extract of Betula alba (Alergia e Inmunologia Abell, S.A.). Schedule started with 1 drop of a 4 STU/mL solution. The dose was increased in a daily manner (1, 2, 4, 6, 8, 10, 10) in order to reach 10 drops at the end of each week. This schedule was repeated with the concentrations 20, 100 and 500 STU/mL after 4 weeks and using the 500 STU/mL solution, the extract was administered every other day (3 times a week for 3 months). Placebo: Saline solution containing 50% glycerine, 0.4% phenol and 0.01% of menthol. Total ocular symptom scores Individual ocular symptom scores (red, watery and itchy eyes) Conjunctival immediate allergen sensitivity Allergen: Betula alba Evaluation post-challenge Potential conicts of interest: Not declared
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. This is not reported in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. The bottles for the treatment and their contents were identical in taste and layout in order to guarantee the double-mask of the trial. Vials content was unknown to the research team and the participants. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods.
Low risk
48
Horak 1998
(Continued)
Low risk
Other bias
Low risk
Khinchi 2004 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Denmark Setting: Specialist care Number randomised: 71 participants Age: Adults (20 to 58 years old) Gender: SLIT: 11 male and 7 female; placebo 12 male and 7 female Inclusion criteria: Participants with at least 2 years of seasonal birch pollen rhinoconjunctivitis uncontrolled by conventional pharmacotherapy were enrolled. Birch pollen allergy was veried by a positive skin prick test and a positive conjunctival provocation test using a standardised extract, and the presence of specic IgE (RAST) class 2) using the CAP System. Participants with mild seasonal birch pollen induced asthma were accepted for inclusion. Exclusion criteria: Perennial allergy, chronic, nonallergic rhinitis or sinusitis, previous immunotherapy with birch pollen within the last 5 years or ongoing immunotherapy with other allergens, treatment with beta-blockers or participants on continuous corticosteroids, pregnancy or planned pregnancy, participation in another clinical trial and the standard contraindications for immunotherapy. SLIT: Active treatment involved a birch pollen extract standardised in terms of the major allergen Bet v 1 administered as glycerosaline solution (SLIT, Staloral; Stallergenes SA, Antony, France). The sublingual treatment was self-administered at home. Drops were held under the tongue for 2 minutes before swallowing. A 30-day sublingual induction phase was followed by a maintenance phase of 21 to 23 months. The initial dose was 0.0164 g and the top dose 49.2 g Bet v 1 administered every second day. The treatment schedule was adjusted according to the individual patients tolerance. Placebo:The placebo preparations included caramelised sugar for sublingual to ensure an identical visual appearance and taste for SLIT preparations. Total ocular symptom scores Ocular medication scores (eye drops) Allergen: Birch pollen Based on the baseline registration 71 participants were allocated into 3 groups: SLITgroup: receiving sublingual immunotherapy (drops) and placebo injections; SCITgroup: receiving subcutaneous immunotherapy (injections) and placebo sublingual drops; Placebo-group: receiving placebo sublingual drops and placebo subcutaneous injections. All study personal and participants were masked to treatment assignment for the 2-year duration of treatment in the study. Potential conicts of interest: Supported by Stallergnes
49
Interventions
Outcomes
Notes
Khinchi 2004
(Continued)
Risk of bias Bias Authors judgement Support for judgement Randomisation was performed by minimisation based on disease severity during the baseline season, gender and age. No details were provided. All study personal and participants were masked to treatment assignment for the 2year duration of treatment in the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Unclear risk
Low risk
Other bias
Low risk
La Rosa 1999 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Italy Setting: Specialist care centre Number randomised: 41 participants Age: Children (6 to 14 years old) Gender: Male 25 and female 16 Inclusion criteria: Participants with a positive history of rhinoconjunctivitis, with or without mild intermittent asthma, caused by Parietaria pollen sensitisation documented by positive skin tests (wheal diameter > 4 mm) and positive radioallergosorbent test results (class II and above). Exclusion criteria: Participants with uncontrolled asthma, symptomatic polysensitisation or who were treated with beta-blockers or long-acting corticosteroids were excluded. Participants with cats at home were also excluded. SLIT: Active treatment consisted of a standardised P judaica extract (Stallergnes, Antony, France) in drops to be taken sublingually and held under the tongue for 2 minutes before being swallowed. The extract was standardised in index of reactivity (IR) units. The level of the Par J 1 major allergen in the 100 IR extract was 70 mg/mL. The build-up treatment phase started with 2 drops of the rst concentration (1 IR/mL), increasing by 2 drops per day up to 10 drops per day, followed by the next concentration (10 IR/mL)
50
Interventions
La Rosa 1999
(Continued)
increasing from 2 to 10 drops per day and then continued with a similar progression from 2 to 20 drops of the next concentration (100 IR/mL) and 2 to 20 drops of the highest concentration (300 IR/mL). After administration of 20 drops of 300 IR per millilitre daily for 1 month, the maintenance dose was 20 drops of 300 IR per millilitre 3 times a week until the end of the study. The cumulative dose of allergen extract received by each patient was 75,000 IR per year. The cumulative dose of Par J 1 major allergen was 52.5 mg over 2 years. Placebo: Placebo consisted of a glycerinated phenolated saline solution with an appearance and taste similar to those of the active treatment. Outcomes Total ocular symptom scores Individual ocular symptom scores (red, watery and itchy eyes) Allergen: Parietaria judaica Potential conicts of interest: Supported by Stallergnes
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. No details were provided. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Low risk
Other bias
Low risk
Moreno-Ancillo 2007 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Spain. Setting: 3 specialist care centres (Cordoba, Madrid and Plasencia) Number randomised: 105 participants Age: Children and adults Gender: Male 55% (n = 58)
51
Moreno-Ancillo 2007
(Continued)
Inclusion criteria: Participants aged 14 to 55 years with at least 1 year of clinical history of moderate-severe seasonal allergic rhinitis to grasses and Olea europaea pollen, with or without asthma symptoms, were recruited. Positive skin prick tests (mean diameter of wheal, 3mm) to grass mix extracts and O europaea were required. Exclusion criteria: Perennial rhinitis or asthma, clinically relevant sensitisation to Dermatophagoides pteronyssinus, Alternaria alternata, cat and/or dog dander, treatment with grass or O europaea allergenic vaccines within the 2 years previous to study initiation, absolute or relative contraindications to immunotherapy, or any other condition that, under the investigators criteria, could compromise the participants safety. Interventions SLIT: Drops. The extract was biologically standardised by major allergens (grass Group 5 and Ole e 1) and quantied in micrograms. Daily dose contained 2 g of grass Group 5 and 3 g of O europaea Ole e 1. Immunotherapy was administered for a mean duration of 248 days, including a preseasonal treatment period of 207 days. Placebo: Placebo was similar in taste and appearance. Total ocular symptom scores Combined ocular symptom and medication scores Allergen: Olea europaea Signicant intra-group symptom reductions in participants receiving SLIT. Potential conicts of interest: ALK-Abell
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement Randomisation in blocks. Asthma diagnosis was a criterion for stratication. It is not reported in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Low risk
Other bias
Low risk
52
Mortemousque 2003 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: France Setting: Specialist care Number randomised: 60 participants Age: Children and adults Gender: Male 20 and female 10 Inclusion criteria: History of perennial conjunctivitis and symptoms after exposition to domestic house dust mites sources. Participants also experienced symptoms not sufciently controlled by topical medications and/or oral antihistamines. IgE-mediated conjunctivitis was demonstrated in all participants selected by positive skin prick tests to D. pteronyssinus (D.pt.) and D. farinae (D.f.) standardised extract, specic IgE (D.pt. and D.f ) positivity (RAST class 2) and CPT positivity to D.pt. Exclusion criteria: Participants sensitised to cat or dog allergens and living with pets at home were excluded. No patient had previously received immunotherapy with D.pt., was using oral steroids or had any other signicant illness. SLIT: Drops. The extract was a D.pt./D.f. preparation in 50% aqueous glycerol. The duration of treatment was 24 months. Treatment was initiated between January 1997 and March 1997 and the study was completed in March 1999. During a 4-week incremental dose period, participants took daily increasing doses from 1 to 10 drops of the 1 IR/mL vial 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 nally 5 to 20 drops of the 300 IR/mL vial during the next 2 weeks. The highest dose (20 drops from the 300 IR/mL vial) was administered daily for 4 weeks and then 3 days per week throughout the maintenance phase. An average cumulative dose of 90 000 IR (equivalent to 2.2 mg of Der p 1 and 1.7 mg of Der f 1) of allergens had been administered to each patient undergoing active treatment by the end of the trial. Placebo: The placebo preparation was identical to active treatment in terms of composition, appearance, presentation, taste and colour. Total ocular symptom scores Conjunctival immediate allergen sensitivity Allergen: Mites Potential conicts of interest: Not declared
Interventions
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. No details were given. Investigators and participants were masked to treatment assignment for the duration of the study.
53
Mortemousque 2003
(Continued)
Low risk
Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Low risk
Other bias
Low risk
Ott 2008 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre. Country: Germany Setting: Specialist care Number randomised: 213 participants Age: Children (11) and adults Gender: Male 71 and female 74 (ITT population) Inclusion criteria: Participants with grass pollen allergic rhinoconjunctivitis. The diagnosis was based on clinical history ( 2 years of grass pollen allergy), conrmed by a positive skin prick test (wheal diameter 3 mm) and the presence of grass pollen-specic serum immunoglobulin (Ig) E reaching a level of at least 0.70 kU/l corresponding to class 2 in the utilised detection system (CAP System; Phadia, Uppsala, Sweden). The skin prick test included 5 grass pollens (cocksfoot or orchard grass, Dactylis glomerata; meadow grass, Poa pratensis; perennial rye grass, Lolium perenne; sweet vernal grass, Anthoxanthum odoratum; and timothy grass, Phleum pratense). Participants had to suffer from persistent allergic rhinitis (> 4 weeks/year) with a severity requiring treatment by drugs recommended for participants with mild persistent rhinitis. All participants had required symptomatic treatment during the course of the preceding pollen season and had planned treatment for the rst study season with either oral cetirizine, ocular or nasal azelastine, oral or ocular prednisolone, nasal beclomethasone or inhaled salbutamol. Exclusion criteria: Perennial allergic rhinitis and/or perennial allergic asthma, a total serum IgE level >2000 kU/l, chronic nonallergic rhinitis or sinusitis, atopic dermatitis, severe asthma (mild asthma grade 1 to 2 was accepted), any immunotherapy in the previous 5 years and the usual contraindications to immunotherapy. House dust mite sensitivity was not an exclusion criterion. SLIT: A mixture of pollen extracts of 5 grasses (cocksfoot or orchard, meadow, perennial rye, sweet vernal and timothy grasses; Staloral, Stallergenes SA, France) was used at a concentration of 300 IR/ml (equivalent to 21 g/ml of Phl p 5; Phleum pratense major allergen) and administered as sublingual drops. Rush titration was performed under close supervision. On day 1, participants took 4 increasing doses of SLIT, corresponding to 30, 90, 150 and 300 IR, at 20 minute intervals (0, 20, 40 and 60 minutes), followed by a 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 character54
Participants
Interventions
Ott 2008
(Continued)
istics were not stated. Outcomes Total ocular symptom scores Individual ocular symptom scores (grittiness, redness, itching, watery eyes) Ocular medication scores Allergen: Grass pollen Potential conicts of interest: Sponsored by Stallergnes GmbH, Germany
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. No details were stated. Investigators and participants were masked to treatment.
Reported in paper.
Low risk
Other bias
Low risk
Palma-Carlos 2006 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Portugal Setting: Specialist care Number randomised: 33 participants Age: Adults Gender: Male 20 and female 13 Inclusion criteria: Participants had to have a clinical history of seasonal (intermittent) rhinoconjunctivitis with or without mild intermittent or mild persistent asthma since at least 2 years. All participants were sensitised to grass pollens, as conrmed by skin prick test and RAST. Exclusion criteria: Participants suffering from severe systemic and/or autoimmune diseases or acquired/congenital immune deciencies, past or current malignancy, neurological or psychiatric disorder requiring major psychodrugs, receiving chronic systemic corticosteroid or beta-blocking treatments were not enrolled, nor were pregnant women.
55
Palma-Carlos 2006
(Continued)
Interventions
SLIT: The IT was performed with a mixture of chemically modied allergenic extracts (carbamylated monomeric allergoid) from grass pollens (Holcus lanatus 33%, Phleum pratense 33%, Poa pratensis 33%) incorporated in oromucosal tablets (Lais, Lofarma S.p.A., Milan, Italy). The tablets had to be dissolved in the mouth in 1 to 2 minutes before swallowing. Enrolment of the participants was preseasonal followed by a seasonal visit in May and an end-of-the year visit in October. Participants were followed during 2 consecutive 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 1000 UA per week, given pre-seasonally till May. Placebo: No details were provided Total ocular symptom scores Allergen: Grass mix Preseasonal schedule; tablets Potential conicts of interest: Lofarma S.p.A
Outcomes Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. No details were stated in the paper. Investigators and participants were masked to treatment but how this was done was not stated. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. 39.4% of participants withdrew during follow-up.
Blinding (performance bias and detection Unclear risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Low risk
Low risk
Other bias
Unclear risk
Panzner 2008 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: Czech Republic Setting: 9 specialist care centres Number randomised: 74 participants (sublingual 20, placebo sublingual 15)
56
Participants
Panzner 2008
(Continued)
Age: Children and adults Gender: Sublingual groups: Male 20 and female 15 Inclusion criteria: All participants had seasonal rhinitis and/or conjunctivitis (without asthma) caused by grass pollen, had experienced symptoms in at least the previous 2 years and 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 tests to standardised pollen extract e Grass mixture I and Dactylis glomerata and the presence of specic IgE to the mixture of grass pollens. Exclusion criteria: Sensitisation to major inhalant allergens coinciding with the grass pollen season e ash (Fraxinus excelsior), lime (Tilia cordata), elderberry (Sambucus nigra), dandelion (Taraxacum ofcinale), plantain (Plantago lanceolata) and nettle (Urtica dioica), systemic immunologic or metabolic disease, malignancies, major anatomic alterations of the upper airways, severe atopic dermatitis, chronic corticosteroid or betablocker treatment, pregnancy, chronic or recurrent inammation of oral mucosa and other contraindications of SIT. Interventions SLIT: Active treatment was a mixture of 6 species of grass pollens (Grass mixture I): oat grass (Arrhenatherum elatius), orchard grass (Dactylis glomerata), fescue (Festuca sp.) , rye grass (Lolium sp.), timothy grass (Phleum pratense) and rye (Secale cereale). The maximal dose (10 drops of 10 000 JSK/ml) contains approximately 1.265 mg of the grass pollen major allergen Lol p I. The treatment was started in autumn and was followed by 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 the tongue for 1 to 2 minutes before swallowing them. According to the schedule, by the end of the trial (September 2004), an average total cumulative dose was more than 580 000 JSK. Placebo: Placebo preparations were identical to the active therapy in composition, appearance, presentation, taste, and colour, but obviously contained no allergen. Allergen: Grass mix Total ocular symptom scores Individual ocular symptom scores (swelling, redness, itching, watery eyes) Participants were randomly allocated to 1 of the following 4 groups: Sublingual active, Sublingual placebo, Supralingual active, Supralingual placebo. Potential conicts of interest: One of the authors is linked to Sevapharma a.s
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement Central randomisation. The randomisation key was generated by the GraphPad Software. Central allocation.
Low risk
57
Panzner 2008
(Continued)
Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Low risk
Other bias
Low risk
Passalacqua 1998 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Italy Setting: Specialist care centre Number randomised: 20 participants Age: Children and adults (age 15 to 46 years old) Gender: Male 7 and female 13 Inclusion criteria: The main inclusion criteria were perennial rhinoconjunctivitis and disease duration of at least 2 years, with or without mild asthma. Sensitisations to allergens other 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, major anatomical alterations of the upper airways, severe atopic dermatitis, were receiving chronic corticosteroid treatment, had previously received immunotherapy, pregnant or lactating women were excluded. SLIT: Treatment started in April, 1994, and continued until March, 1996. Immunotherapy consisted of tablets of monomeric allergoid Dermatophagoides pteronyssinus and D farinae (LAIS, Laboratorio Farmaceutico Lofarma, Milan, Italy). The tablets were placed under the tongue, dissolved in the mouth for 1 to 2 minutes, and swallowed. The buildup 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 alternate days. In the maintenance phase, participants received 2000 AU twice weekly. Placebo: The placebo tablets were identical to immunotherapy in avour and appearance. Total ocular symptom scores Allergen: Mites Potential conicts of interest: Not declared
Interventions
Outcomes Notes
Risk of bias
Passalacqua 1998
(Continued)
Bias
Authors judgement
Support for judgement Random codes were used.
It was not stated in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. Reported in paper.
Low risk
Other bias
Low risk
Passalacqua 1999 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Italy Setting: Specialist care centre Number randomised: 30 participants Age: Adults Gender: Male 19 and female 11 Inclusion criteria: All participants had seasonal rhinoconjunctivitis (13 with mild intermittent asthma) caused by Parietaria pollen and had experienced symptoms in at least the 2 previous years. Other sensitisations were excluded by skin testing and RAST (panel including 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. No pregnant or lactating women were admitted. SLIT: The SLIT (ALK-Abell) was administered pre-seasonally (from October 15 to March 15, 1996), according to a rush schedule. The diary card was recorded again during the 1996 pollen season. The extract in glycerinated-phenolated aqueous solution was prepared in 5 different vials at increasing concentrations (0.016, 0.08, 0.4, 2, and 10 BU/mL). During the build-up, the drops had to be taken twice daily, starting with 1 drop from the rst vial and increasing up to 5 drops and then repeating the procedure with each vial until the maximum dose was reached (5 drops from the 10-BU/mL vial) . This maintenance dose (corresponding to 0.12 g of Par j 1) was then administered
59
Interventions
Passalacqua 1999
(Continued)
daily until the beginning of the pollen season. The cumulative dose was 256 BU (about 16 g of Par j 1). Placebo: The placebo was undistinguishable from the active treatment. Outcomes Total ocular symptom scores Individual ocular symptom scores (red and itchy eyes) Allergen: Parietaria judaica Potential conicts of interest: Two authors are linked to ALK-Abell Group, Milan, Italy
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. It was not stated in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Low risk
Other bias
Low risk
Passalacqua 2006 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: Italy Setting: Specialist care centres Number randomised: 68 participants Age: Adults Gender: Male 28 and female 40 Inclusion criteria: Participants had to suffer from mild persistent rhinitis according to ARIA guidelines with or without mild intermittent asthma according to Global Initiative on Asthma (GINA) guidelines since at least 2 years. They had to have a skin positivity to house dust mite (wheal diameter > 5 mm) and a CAP - radioallergosorbent class II or greater.
60
Participants
Passalacqua 2006
(Continued)
Exclusion criteria: (i) systemic immunological disorders; (ii) malignancies; (iii) diabetes; (iv) chronic heart failure or chronic obstructive pulmonary disease; (v) pregnancy or lactation; (vi) skin test positivity to cat/dog dander or Parietaria (this latter allergen is almost perennial in the Mediterranean area); (vii) any specic IT course in the last 5 years and (viii) major psychiatric disorders. Interventions SLIT: Sublingual immunotherapy was a monomeric carbamylated allergoid (Lais - Lofarma S.p.A, Milan, Italy) biologically standardised in allergenic units (AU), and prepared as soluble tablets. The tablets had to be taken in the morning on an empty stomach, 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 1000 AU. Subsequently, that maintenance dose of 1000 AU was administered 2 times a week for 2 years continuously. Placebo: Placebo tablets contained the same excipients without the allergoid and were undistinguishable in aspect, avour and dissolution time from the active treatment. Individual ocular symptom scores (Itchy eyes) Allergen: Mites Potential conicts of interest: Lofarma S.p.A
Outcomes Notes
Risk of bias Bias Authors judgement Support for judgement A computer-generated list was used.
It is not stated in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. Reported in paper.
Low risk
Other bias
Low risk
61
Pfaar 2008 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: Germany, Poland and Macedonia Setting: 11 specialist care centres Number randomised: 185 participants Age: Adults (17 to 59 years old) Gender: Male 116 and female 69 Inclusion criteria: 1) diagnosed as having IgE-mediated grass pollen allergic rhinitis or rhinoconjunctivitis, with or without bronchial asthma (Global Strategy for Asthma Management and Prevention program I or II criteria); 2) the existence of a positive skin prick test wheal result with a 6 grass pollen extract equal to or greater than the histamine control (0.1%) or greater than 5 mm in diameter; 3) the existence of a positive radioallergosorbent test result or of CAP enzyme allergosorbent test class 2 or greater ( 0.7 kU/L); 4) a positive conjunctival provocation test result with grass pollen allergens; and (5) reported rhinitis or conjunctivitis symptoms during the baseline season (participants must have had a symptom score of 4 from a possible maximum of 30 on each day in the week after the peak pollen count). Exclusion criteria: Exclusion criteria were as follows: previous grass pollen immunotherapy, symptoms related to or positive skin prick test result at least as large as the histamine control or greater than 5 mm in diameter to other allergens relevant in the grass pollen season (e.g. tree pollen, weeds, moulds, cat, or mites), pregnancy, intake of beta-blockers or angiotensin-converting enzyme inhibitors, long-term treatment with systemic corticosteroids or long-acting antihistamines, intake of long-acting beta 2-agonists or nasal corticosteroids during the grass pollen season, and cardiovascular, immunological, or other medically relevant diseases. SLIT: It contained pollen allergens of 6 grass species (Holcus lanatus, Dactylis glomerata, Lolium perenne, Phleum pratense, Poa pratensis, and Festuca elatior). The allergen extract was standardised to the content of the group 5 grass allergen. The group 5 allergen content of the maintenance dose was 40 g, as measured in 1 enzyme-linked immunosorbent assay (ELISA) system, and 20 g, as measured with a recombinant reference preparation and assay, as tested in the CREATE project. The latter is most likely to conform to a future biological reference system. The study solution was applied to and kept under the tongue for 3 minutes and swallowed thereafter. Dose escalation was performed at the investigators site on the rst day of treatment, with a doubling of the dose every 60 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 g of the group 5 grass allergen. This was followed by daily self-administration of the maintenance dose by the participant. If the full maintenance dose was not tolerated, the dose was temporarily reduced to 75%, 50%, 25%, or 0% and readjusted individually, if possible, to the full dose after consultation with the study physician. The baseline evaluation was during the grass pollen season in 2003 and a treatment phase from January 2004 until the end of the grass pollen season in 2005. Placebo: Matching placebo was identical in colour, taste, and smell and did not contain active ingredients. AUC of the ocular symptom-medication-score (SMS)
Participants
Interventions
Outcomes
62
Pfaar 2008
(Continued)
Notes
Allergen: Grass mix Potential conicts of interest: Supported by Allergopharma
Risk of bias Bias Authors judgement Support for judgement A block randomisation was performed, and there was a stratication procedure with respect to asthma. Central allocation. Investigators and participants were masked to treatment assignment for the duration of the study. Reported in paper.
Low risk
Low risk
Other bias
Low risk
Pradalier 1999 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: France Setting: 20 specialist care centres (Paris area 5, Nantes 9, Orlans 2, Valence 3, Le Creusot 1) Number randomised: 126 participants (ITT, n = 123) Age: Children (17) (7 to 15 years old) and adults (109) Gender: Male 65 and female 58 Inclusion criteria: Participants had to have grass pollen related seasonal rhinitis, allergic conjunctivitis or mild asthma. The diagnosis of grass-pollen allergy was based on a suggestive clinical history, a positive prick test to 1 of the pollens in the 5 grass pollen extract (Stallergnes SA, Antony, France), and a positive assay for specic IgE to orchard grassor timothy grass with the CAP System. Exclusion criteria: Clinically relevant sensitisation to house dust mites (Dermatophagoides pteronyssinus/D. farinae), cockroach, Alternaria, and pollens released during the same season as grass pollens. Allergy to cat and/or dog dander was an exclusion criterion only if the pet lived in the participants home. Asthmatic patients whose treatment included medications other than beta 2-agonists taken as needed were excluded, as
Participants
63
Pradalier 1999
(Continued)
were participants who had received immunotherapy with 1 of the pollens in the 5 grass pollen extract within the last 2 years. Interventions SLIT: The standardised 5 grass pollen extract (Stallergnes SA, Antony, France) used throughout the study was a mixture of orchard grass, meadow grass, ryegrass, sweet vernal grass, and timothy grass pollens. Its biologic activity was evaluated with RAST inhibition in comparison with an internal standard in in vitro and in vivo tests, and was expressed as the index of reactivity (IR) dened as follows: a prick test with an extract containing 100 IR/ml produces a wheal with a mean geometric diameter of 7 mm in 30 participants sensitised to the allergen under consideration. The amount of the timothy major allergen Phl p 5 in 100-IR extract was 8.5 g/mL. The study treatment was given from March 1996 to July 1996. The treatment included a 15-day progression of doses phase (Table 1), during which the extract was given each morning as sublingual drops prepared with a glycerosaline diluent (Stallergnes SA, Antony, France) containing 1, then 10, and nally 100 IR/ml. The participants were instructed to keep the drops under the tongue for 2 minutes before swallowing them. When the 100-IR dose was reached (20 drops from the 100-IR/ml bottle), the drops were replaced by once-daily administration of a single sublingual tablet containing 100 IR, until 7 July 1996. The cumulative allergen dose in the active treatment group was about 11 000 IR corresponding to 0.935 mg of the timothy pollen major allergen Phl p 5. Placebo: The placebo drops and tablets were similar to the active agent in terms of appearance, taste, and packaging. In both groups, the extract as sublingual drops was a limpid, colourless solution, with a sweet taste and smell. Active and placebo tablets were white, with a slightly sweet taste but no smell. Total ocular symptom scores Individual ocular symptom scores (grittiness, redness, itching, watery eyes) Ocular medications scores (eye drops) Allergen: Grass mix Drops and tablets Potential conicts of interest: Two authors are linked to Stallergnes
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. No details were provided in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods.
64
Pradalier 1999
(Continued)
Low risk
Other bias
Low risk
Purello-D Ambrosio 1999 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Italy Setting: Specialist care centre Number randomised: 30 participants Age: Adults Gender: Male 14 and female 16 Inclusion criteria: Participants were enrolled if they had had symptoms of allergic rhinoconjunctivitis with or without moderate asthma (FEV1 values of 7090% of predicted values) for at least 2 years during the Parietaria pollen season and a skin prick test positive for the P. judaica. Specic IgE to P. judaica levels in sera were determined by the RAST EIA technique (Pharmacia Diagnostics AB, Uppsala, Sweden), and only participants showing at least a class 3 result were selected for the trial. Exclusion criteria: Exclusion criteria were severe asthma (FEV1 values below 70% of predicted values), previous specic immunotherapy, sensitisation to other inhalant allergens, pregnancy, or other general contraindications for immunotherapy as established in the EAACI position paper. SLIT: The therapy consisted of 5 3-ml vials with a concentration of 0.016 BU/ml (vial 0), 0.08 (vial 1), 0.04 (vial 2), 2 (vial 3), and 10 (vial 4) in physiologic saline with 50% v/v of glycerol and 0.4% w/v of phenol. The major allergen Par j 1 content in the vial with the maximum concentration was 0.6 g/ml. The treatment schedule was started in January, before the beginning of the P. judaica pollination period, after a 2week rush-inducing schedule. The drops were to be taken from the different vials, and had to be taken twice daily, starting with 1 drop from vial 0 and increasing by 1 drop at each administration up to a dose of 5 drops of the same vial and then repeating the procedure with the subsequent vials. The maximum dose of 5 drops from vial 4 was then administered 3 times a week. This maintenance dosage was continued until the end of September. According to the schedule, by the end of the trial, an average cumulative dose of 199.5 BU of allergen had been administered to each patient in the active sublingual therapy group, equal to 12.77 g of Par j 1. Placebo: Placebo preparations were identical to the active therapy in composition, appearance, presentation, taste, and colour. Total ocular symptom scores Individual ocular symptom scores (itching and red eyes) Allergen: Parietaria judaica Potential conicts of interest: Two authors are linked to ALK-Abell
65
Interventions
Outcomes
Notes
Purello-D Ambrosio 1999
(Continued)
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. No details were provided in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Low risk
Other bias
Low risk
Rolinck-Werninghaus 2004 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: Germany Setting: 4 specialist care centres (Berlin, Freiburg, Dresden, Munich) Number randomised: 97 participants Age: Children Gender: Male 65 and female 32 Inclusion criteria: Children aged 3 to 14 years with seasonal allergic rhinitis with specic IgE to grass pollen (CAP-class 2), a wheal size of 3 mm or a skin index of 0.6 in SPT, and a positive CPT at a specic allergen concentration 100 000 SQ-U/ml. Exclusion criteria: Exclusion criteria were perennial asthma with a need for permanent topical or systemic corticosteroid treatment, atopic dermatitis with a need for permanent treatment with corticosteroids, systemic treatment with corticosteroids or immune suppressive drugs within the 4 weeks before the start of the study, perennial allergic rhinitis, treatment with SIT within the 3 years before the start of the study and the known contraindications of SIT according to the EAACI position paper. SLIT: Participants in the active group were treated with standardised allergens from a 5 grass mixture composed of Dactylis glomerata, Festuca pratensis, Lolium perenne, Phleum pratense and Poa pratensis in equal parts suspended in physiologic saline solution with 50% glycerol and 0.3% phenol (Pangramin SLIT; ALK-SCHERAX, Hamburg,
66
Participants
Interventions
Rolinck-Werninghaus 2004
(Continued)
Germany). The potency was expressed in specic treatment units (STU); 1000 STU were equivalent to 25 biological units (BU) and contained 2.5 g of major grass pollen allergens. The monthly dose during maintenance treatment was 6 g (0.5 g/dose, 3 times/week). The median for the total duration of treatment was 32 months (January 1999 to November 2001) with a median cumulated dose of 188 g allergens. Children were instructed to applicate the relating amount of the SLIT preparation under the tongue and to wait for 3 minutes before swallowing. Initial treatment of SLIT was applied from 5 vials (0 to 4) with the concentrations 1.6, 8, 40, 200 and 1000 STU/ml beginning with 1 drop from vial 0 taken on days 1 and 2 and continued by 2 drops on days 2 and 3 until reaching 5 drops on days 9 and 10. The dose was then increased by 1 drop/day from 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 until the end of the 32 months treatment period. Placebo: Placebo vials contained the Pangramin solution without allergen. Outcomes Total ocular symptom scores Individual ocular symptom scores (grittiness, redness, itching, watery eyes) Conjunctival immediate allergen sensitivity Allergen: Grass mix The adjusted symptom scores (to 1000 pollen/m3) in 6 weeks with peak pollen counts in the third grass pollen season were included Potential conicts of interest: Alk-Scherax
Notes
Risk of bias Bias Authors judgement Support for judgement Randomisation was conducted for age and history of asthma in consecutive order at inclusion. Central allocation. Investigators and participants were masked to treatment assignment for the duration of the study. Reported in paper.
Low risk
Low risk
Other bias
Low risk
67
Rder 2007 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: The Netherlands Setting: Primary care (64 general practices) Number randomised: 204 participants Age: Children (6 to 17 years old) Gender: ITT population: Male 95 and female 73 Inclusion criteria: Inclusion criteria were IgE antibodies to grass pollen 0.7 kU/L and a history of rhinoconjunctivitis, assessed by a retrospective symptom score: participants scored 5 symptoms (sneezing, itching nose, watery running nose, nasal blockage, and itching 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). Participants with a retrospective total symptom score 5 were included. Exclusion criteria: Exclusion criteria included the use of daily pulmonary inhaled glucocorticoids during 3 months in the preceding year, immunotherapy in the preceding 3 years, sensitisation to pets in the family home (specic IgE 0.7 kU/L), nasal abnormalities requiring surgery, and contraindications for immunotherapy. SLIT: Participants underwent verum treatment with a mixture of aqueous extracts of 5 grass pollen species (Lolium perenne, Phleum pratense, Dactylis glomeratein, Anthoxantum odoratum, and Holcus lanatus; Oralgen Grass Pollen; Artu Biologicals, Lelystad, The Netherlands) in a glycerinated isotonic phosphate-buffered solution. Treatment starting with a single drop containing 475 biological units (BU) of allergen was increased with 1 drop daily until day 20. The maintenance dose was 20 drops (9,500 BU; 21 g equivalent Lol 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 there for at least 1 minute before being swallowed. Placebo: Placebo treatment consisted of the solvent. Individual ocular symptom scores (itchy eyes) Allergen: Grass mix Potential conicts of interest: Supported by Artu Biologicals
Participants
Interventions
Outcomes Notes
Risk of bias Bias Authors judgement Support for judgement A computer-generated randomisation list stratifying for symptom score and participating general practice was utilised. A pharmacist allocated medication in accordance with a computer-generated randomisation list stratifying for symptom score and participating general practice. Participants, parents, investigators, and caregivers were unaware of the group as68
Low risk
Rder 2007
(Continued)
signment and could not make a distinction between verum and placebo treatment. Blinding (performance bias and detection Low risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Low risk Investigators and participants were masked to treatment assignment for the duration of the study. Reported in paper.
Low risk
Other bias
Low risk
Sanchez-Palacios 2001 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Spain Setting: Specialist care centre Number randomised: 40 participants Age: Adults Gender: Male 16 and female 24 Inclusion criteria: Symptoms of perennial rhinitis and/or asthma associated with cat exposure, monosensitisation to cat, positive nasal challenge test to cat epitelia. Exclusion criteria: Polysensitised patients, previous course of immunotherapy, poor compliance suspicion. 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, 0.02 and 1 HEP equivalent/mL. Saline solution, glycerine 50% and phenol 0.4% was used as vehicle. SLIT was provided daily and kept under the tongue for 3 minutes. After 1 year of treatment the cumulative dose was 3.6 g of Fel d 1. Placebo: Saline solution, glycerine 50% and phenol 0.4%. Total ocular symptom scores Individual ocular symptom scores (red, itchy, watery eyes) Ocular medication scores (eye drops) Allergen: Cat Potential conicts of interest: Not declared
Interventions
Outcomes
Notes
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Sanchez-Palacios 2001
(Continued)
Participants were randomised but how this was done was not stated. No details were provided in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. No details were provided in the paper.
Blinding (performance bias and detection Low risk bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Selective reporting (reporting bias) Unclear risk
Low risk
Other bias
Low risk
Smith 2004 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: United Kingdom Setting: General practice setting Number randomised: 180 participants Age: Adults Gender: Male 48 and female 41 (per protocol population) Inclusion criteria: Adults (18 to 60 years) were eligible if their seasonal rhinitis was not well controlled in previous years, despite prescription of nasal steroids and/or oral antihistamines, together with evidence of grass pollen sensitisation (skin prick wheal diameter 4 mm and IgE RAST class 2). Exclusion criteria: Exclusion criteria were perennial rhinitis, asthma (except for peak seasonal wheezing), other signicant medical illness, anticipation of difculty attending follow-up, treatment with beta-blockers or systemic corticosteroids, and pregnancy or planned pregnancy. SLIT: Each year, treatment started in February with increasing daily doses of grass pollen extract (orchard, meadow, rye, sweet vernal, and timothy grasses) followed by maintenance therapy until July 31. The extract was standardised in IR units: 100 IR/mL was dened as the concentration eliciting a mean skin prick wheal diameter of 7 mm in 30 sensitised participants. The quantity 100 IR contained 24 g Lol p 1 and 14 mg Dac g 5. Participants received increasing doses starting with 1 drop of 1 IR/mL and increasing to 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). The cumulative 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.
70
Participants
Interventions
Smith 2004
(Continued)
Outcomes
Total ocular symptom scores Individual ocular symptom scores (itching, watery eyes) Conjunctival immediate allergen sensitivity Allergen: Grass mix One group received active treatment for 2 years, 1 group received 1 year of active treatment and then placebo, and the third group received placebo in both years. Potential conicts of interest: Supported by Stallergnes and one of the authors is linked to Stallergnes France
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. Authors stated that groups were checked for homogeneity regarding demographics, symptom scores, and relevant clinical parameters. Investigators and participants were masked to treatment assignment for the duration of the study. Placebo tablets and drops were physically identical to active medication. Reported in paper.
Low risk
Low risk
Other bias
Low risk
Torres-Lima 2002 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: United Kingdom Setting: Specialist care centre Number randomised: 56 participants Age: Adults (21 to 53 years old) Gender: Male 32 and female 24 Inclusion criteria: All participants gave a history of seasonal allergic rhinoconjunctivitis of at least 2 years duration and a positive skin-prick test (weal diameter > 5 mm) to timothy grass pollen extract. Participants with mild seasonal asthma were included, provided their
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(Continued)
symptoms were controlled by inhaled beta 2-agonist alone. Exclusion criteria: Participants were excluded if they gave a clinical history of other allergies, had received immunotherapy in the previous 5 years or had any other signicant medical illness. Allergy to cat and/or dog was an exclusion criteria only if participants had daily contact with pets. Participants with chronic asthma were excluded. Interventions SLIT: The immunotherapy treatment was Soluprick SQ (ALK Abell), a standardised extract of Phleum pratense (timothy grass pollen) diluted in 50% glycerol. The concentration of grass pollen allergen extract was 1 mg/mL. The duration of treatment was 12 to 18 months. The treatment schedule comprised a 6-week up-dosing phase followed by 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 availability of resuscitative measures. Maintenance doses were taken at home. Up-dosing involved 3 visits per week, with 1 drop (25 g of Phleum pratense extract) administered per visit in the rst 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 g of Phleum pratense extract per month), giving a cumulative monthly dose of major allergen (Phl p 5) of approximately 900 g, equivalent to 40 to 50 times the amount contained in the usual monthly maintenance injections via the subcutaneous route. Drops were kept under the tongue for 3 minutes before swallowing. Placebo: It was identical to the extract in appearance, presentation, taste and colour. Conjunctival immediate allergen sensitivity Allergen: Phleum pratense Potential Conicts of interest: Supported by ALK-Abell
Outcomes Notes
Risk of bias Bias Authors judgement Support for judgement Randomisation to active or placebo treatment was performed by the manufacturer of the grass pollen vaccine using a system of computer-generated random numbers in blocks of 12. Central allocation. The treatment schedule and assessments were performed double-masked, with treatment allocations kept in sealed envelopes by the principal investigator. Reported in paper.
Low risk
Low risk
Low risk
The specied outcomes in the methodology were reported in the results section.
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Torres-Lima 2002
(Continued)
Other bias
Low risk
No other sources of bias were detected or suspected.
Troise 1995 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Italy Setting: Specialist care centre Number randomised: 31 participants Age: Adults Gender: Male 12 and female 19 Inclusion criteria: 1) Severe symptoms of rhinitis without asthmatic manifestations during the Parietaria pollen season for at least 2 consecutive years, 2) positive skin prick test only to Parietaria judaica at the concentration of 100 BU/mL and 3) positive RAST for Parietaria class III or more. Exclusion criteria: Participants were ineligible if they had a disease that could interfere with the evaluation of clinical symptoms, such as rhinitis medicamentosa, sinusitis or large obstructive nasal polyps; pregnancy or nursing; not taking adequate female contraception, had serious cardiac, pulmonary, renal, hepatic, neurological or malignant disease, or were travelling outside the pollen area for more than 1 week. SLIT: Treatment was initiated in January 1991 before the Parietaria pollen season and continued for 10 months. Active therapy contained an aqueous extract of Parietaria judaica pollen in physiological saline and 50% glycerol preserved with 0.4% w/v phenol. The aqueous extract was provided in 5 vials (0 to 4) at vefold increasing allergen concentrations from 0.008 up to 5 BU/mL in the highest-concentration vial. The participants received increasing doses from each vial starting with 1 drop from vial 0 and increasing by 1 drop every 2 days to 5 drops by the ninth and the tenth days. This schedule was repeated with the other vials, increasing by 1 drop daily to 5 drops by the fth day. The duration of the build-up period was 30 days, followed by maintenance therapy 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 105 BU containing about 6.3 g of the major allergen of P. judaica (Par j 1) was administered to each participant on the active treatment for 10 months. Placebo: Consisted of saline solution in identical vials, with colour and similar taste to the active product. Total ocular symptom scores Individual ocular symptom scores (itching and red eyes) Ocular medication scores (eye drops) Allergen: Parietaria judaica Potential conicts of interest: One of the authors is linked to Neo-Abell, Milan, Italy
Interventions
Outcomes
Notes
Risk of bias
73
Troise 1995
(Continued)
Bias
Authors judgement
Support for judgement Participants were randomised but how this was done was not stated. It was not specied in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Low risk
Other bias
Low risk
Valovirta 2006 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Finland Setting: Specialist care centre Number randomised: 98 participants Age: Children Gender: ITT: Male 31 and female 25 (dose 2 and placebo) Inclusion criteria: Age 5 to 14 years; clinical history of tree pollen-induced allergic rhinoconjunctivitis with/without seasonal asthma for at least 2 years; Positive specic IgE 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 methacholine PD20 150 g; Tree pollen allergy responsible for the majority of clinical symptoms. Exclusion criteria: Perennial allergic symptoms; Clinically important symptoms of food allergy unless they are unsymptomatic with elimination diet; Clinically important history of house dust mite and/or mould allergy; Positive SPT 3 mm to Dermatophagoides pteronyssinus, Dermatophagoides farinae and Cladosporium herbarium, Alternaria alternata; Daily contact with any pet to which the patient is sensitised; Any other clinically signicant disease (as judged by the investigator) that might affect the outcome of the trial or the patients health; Treatment with beta-blockers or ACE inhibitors; Non allergic chronic rhinitis or sinusitis; Previous immunotherapy with any tree pollen extracts within the last 5 years; Treatment with long-acting beta 2-agonist and/or antileukotrienes; FEV1
74
Valovirta 2006
(Continued)
< 70% and PEF < 80% of predicted normal value; Severe atopic dermatitis; Seasonal asthma requiring more than 400 g budesonide/day, 400 g beclomethasone / day, 200 g uticasone/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 of 1,000,000 SQ-U/ml (100 HEP) contains: 1.00 mg B. verrucosa, 1.40 mg C. avellana and 1.00 mg A. glutinosa corresponding to a major allergen content of 150 g (Bet v 1/Aln g 1/Cor a 1). Sublingual immunotherapy was carried out at home. The study medication was a uid in multiple-use vials. Each dose consisted of 10 drops (400 l). Treatment was administered 5 times per week with a 5-week up-dosing phase and a maintenance period of up to 18 months. The dose was administered sublingually and kept under the tongue for 3 minutes and then swallowed. The children were randomised equally to 1 of the 3 following groups: (i) Dose group 1: the active study medication for dose group 1 was, 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 SQU/ml. The accumulated weekly dose corresponded to 24,000 SQ-U or 3.6 g major allergen Bet v 1/Aln g 1/Cor a 1. (ii) Dose group 2: the active study medication for this 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 of 100 000 SQ-U/ml. The accumulated weekly dose corresponded to 200,000 SQ-U or 30 g major allergen Bet v 1/Aln g 1/Cor a 1. Placebo: The placebo medication was, for the up-dosing and maintenance phase, a diluent containing 50% glycerol and 50% saline buffer. Total ocular symptom scores 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) were included in the efcacy analyses Potential conicts of interest: Two of the authors are linked to ALK-Abell
Outcomes Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. Central allocation. The study was conducted under doublemasked conditions. There was no difference in colour and viscosity between the study drug and placebo. All masking procedures were performed by the Quality Assurance Department at ALK-Abell A/S.
Random sequence generation (selection Unclear risk bias) Allocation concealment (selection bias) Low risk
75
Valovirta 2006
(Continued)
Low risk
Reported in paper.
Low risk
Other bias
Low risk
Vervloet 2007 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: France Setting: Specialist care centre Number randomised: 76 participants Age: Adults (19 to 60 years old) Gender: Male 39 and female 37 Inclusion criteria: Participants had to have typical symptoms of rhinoconjunctivitis, possibly associated with moderate asthma, during the cypress pollen season (January, February, March). Sensitisation was conrmed by positive skin prick test to C. sempervirens or C. arizonica and to J. ashei extracts and serum specic antibody levels to J. ashei and Cupressus greater than or equal to class 2 as determined by CAP. Exclusion criteria: Perennial allergic rhinoconjunctivitis to mites or cockroaches; severe intermittent or persistent asthma; participants sensitised to cat or dog dander and living with pets at home. Patients previously treated with immunotherapy or beta-blockers were excluded. Other exclusion criteria were the known contraindications to immunotherapy according to the EAACI guidelines. SLIT: A puried standardised J. ashei extract was manufactured by Stallergnes (Antony, France). The Jun a 1 major allergen content was 76 g/ml of the 100 IR allergen extract. Sublingual therapy was graded in a single concentration of 300 IR/ml (equivalent to 30 histamine equivalent potency, HEP) in 50% glycerol aqueous solution. The treatment was started on day 1 with a titration within 90 minutes (30-90-150-300 IR). Maintenance treatment (300 IR) was given once a day before breakfast for 120 days in a one-off treatment. This daily dose in maintenance treatment corresponded to 228 g Jun a 1. In the 2001 protocol, indwelling intravenous lines were used in all cases during the ultrarush procedure. Placebo: Placebo consisted of 50% glycerol aqueous solution. Total ocular symptom scores Individual ocular symptom scores (itchy, watery and red eyes) Ocular medication scores (eye drops) Allergen: Juniperus ashei In order to analyse about 80 participants, participants were enrolled in the trial in both 2001 and 2002. Potential Conicts of interest: Supported by Stallergnes
76
Interventions
Outcomes
Notes
Vervloet 2007
(Continued)
Risk of bias Bias Authors judgement Support for judgement Randomisation in blocks was used.
No details were provided in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Low risk
Other bias
Low risk
Voltolini 2001 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Italy Setting: Specialist care centre Number randomised: 30 participants Age: Adults (17 to 64 years old) Gender: Male 11 and female 19 Inclusion criteria: Clinical history of at least 2 years of seasonal rhinoconjunctivitis, with or without intermittent to moderate persistent asthma (21); sensitisation to Betulaceae/ Corylaceae pollens conrmed 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 specic immunotherapy within the last 5 years; sensitisation to other inhalant allergens; pregnancy in progress or already planned; chronic or recurrent inammation of the oral mucosa. SLIT: The active specic immunotherapy consisted of a mixture 1:1:1 of 3 biologically standardised 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/mL correspond to 66 g/mL of the major allergen Bet v 1. A rush pre-seasonal treatment schedule was followed. Drops were taken sublingually twice a day, morning and evening for 18 days starting from 1 drop of strength 0.04 BU/mL up to 5 drops of the same vial. The same procedure was repeated to reach the top dose of 5 drops of strength 100
77
Interventions
Voltolini 2001
(Continued)
BU/mL. Each allergen dose had to be kept in the mouth for at least 2 minutes and then anything remaining in the mouth had to be swallowed. The treatment started in the middle of December 1997 so that the maximum dose was reached before the beginning of the pollen season and repeated 5 days a week (Monday to Friday) for 1 month. A coseasonal maintenance treatment followed, at a dosage of 5 drops of strength 25 BU/mL 3 times a week until the end of the pollen season. The cumulative dosage received by each participant was therefore 819 BU in 5 months on average. For birch extract, this amount corresponds to around 445 g 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) and 0,3% phenol (W/V). Outcomes Total ocular symptom scores Individual ocular symptom scores (itching and red eyes) Ocular medication scores (eye drops) Allergen: Tree pollens - Mix of Betulaceae/Corylaceae (alder, birch and hazel) The study followed a double-masked, placebo controlled design during the rst year and an open-controlled design during the second year Potential conicts of interest: Two of the authors are linked to ALK-Abell
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. No details were provided in the paper. Investigators and participants were masked to treatment assignment for the duration of the study. Placebo was prepared as saline solution in vials with exactly the same appearance, colour and taste, but without allergens, in order to guarantee the doublemasked design of the trial. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. Insufcient information to assess whether an important risk of bias exists.
Low risk
Low risk
Other bias
Unclear risk
78
Vourdas 1998 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Greece Setting: Specialist care centre Number randomised: 66 participants Age: Children Gender: Male 49 and female 17 Inclusion criteria: Participants with a positive history of rhinoconjunctivitis and/or mild asthma due to sensitisation to olive pollen proved by positive skin prick tests and positive RAST class II and above were included. Exclusion criteria: Participants who had uncontrolled asthma or symptomatic polysensitisation, or who were taking beta-blockers or retard corticosteroids were excluded. SLIT: The study ran for 2 consecutive years (October 1994 to October 1996), the sublingual therapy being administered pre- and co-seasonally from January to July each year. The active treatment was a standardised olive pollen extract (Stallergenes SA). The major allergen Ole e 1 was 13.5 ig/ml (100 IR/ml). Four concentrations of the allergen were used: 1, 10, 100, and 300 IR/ml. Participants received drops to be taken each morning 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 (1 IR/ml), increasing by 2 drops per day up to a maximum of 10 drops/day. The treatment continued with 2 drops of the next concentration (10 IR/ml), increasing by 2 drops per day up to 10 drops/day, and then progressing in a similar way from 2 to 20 drops of the next concentration (100 IR/ml) and then of the highest concentration (300 IR/ml). The maintenance dose was 20 drops of 300 IR/ml daily for 5 months. In July, the treatment was stopped until the next January. The same schedule was used for the second season of the trial. The cumulative dose of allergenic extract received by each patient was 30 000 IR per year (300 times higher than in parenteral specic immunotherapy). The cumulative dose of major allergen Ole e 1 was 4.05 mg/year. Placebo: The placebo was a glycerinated phenolated saline solution with an appearance similar to that of the active agent. Total ocular symptom scores Individual ocular symptom scores (red, itchy and watery eyes) Allergen: Olea europaea Potential conicts of interest: Three of the authors are linked to Stallergnes France
Interventions
Outcomes
Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised but how this was done was not stated. No details were provided in the paper.
79
Vourdas 1998
(Continued)
Investigators and participants were masked to treatment assignment for the duration of the study. The placebo was a glycerinated phenolated saline solution with an appearance similar to that of the active agent. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. No other sources of bias were detected or suspected.
Low risk
Low risk
Other bias
Low risk
Wahn 2009 Methods Study design: Randomised, parallel, double-masked and placebo controlled clinical trial, multicentre Country: France, Spain, Germany, Poland and Denmark. Setting: 29 specialist care centres in 5 countries Number randomised: 278 participants Age: Children Gender: Female to male: 36% to 64% Inclusion criteria: Children and adolescents 5 to 17 years of age. All participants had grass pollen-related moderate-to-severe allergic rhinoconjunctivitis for at least 2 years conrmed by means of a positive skin prick test response (wheal diameter, > 3 mm) and a timothy grass pollen-specic IgE level of at least class 2 ( 0.7 kU/L); had a score of at 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 grass pollen season caused by sensitisation to allergens other than grass pollen, including perennial allergens causing rhinitis symptoms, asthma requiring treatment other than beta 2 inhaled agonists; participants who had received any desensitisation therapy for grass pollen; and the usual contraindications for specic immunotherapy, such as concomitant beta-blocker therapy, severe and/or stable asthma, severe immune deciency or autoimmune disease, or malignancies. 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 used for the study. A 300-IR tablet corresponded to approximately 20 mg of the group 5 major allergens. Placebo: The placebo tablet matched the active treatment in size, shape, and colour but contained no active ingredients. Excipients were identical to those in the active treatment
80
Participants
Interventions
Wahn 2009
(Continued)
tablets, with the addition of caramel and quinoline yellow. Outcomes Total ocular symptom scores Individual ocular symptom scores (red, itchy and watery eyes) Allergen: Grass pollen Potential Conicts of interest: Supported by Stallergnes
Notes
Risk of bias Bias Authors judgement Support for judgement The randomisation list was stratied by study centre and organised in blocks. Central allocation. Investigators and participants were masked to treatment assignment for the duration of the study. Excipients used in both active and placebo tablets include lactose, sodium stearate, and sodium croscarmellose. Reported in paper.
Low risk
Low risk
Other bias
Low risk
Wuthrich 2003 Methods Participants Study design: Randomised, parallel, double-masked and placebo controlled clinical trial Country: Switzerland Setting: Five specialist care centres Number randomised: 28 participants Age: Children (4 to 11 years old) Gender: Male 20 and female 8 Inclusion 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/or specic IgE (RAST/CAP) to grass pollen. Exclusion criteria: History of allergic rhinitis/asthma during the spring (March to April corresponding to tree pollinosis) and/or perennial rhinitis or asthma or severe atopic dermatitis.
81
Wuthrich 2003
(Continued)
Interventions
SLIT: The schedule of treatment included the daily administration of the drops until the maintenance dose was reached, beginning with 1 drop from vial 0 on the rst day and second day, increasing by 1 drop every 2 days, and culminating with 5 drops on the ninth and tenth days. The administration from the vials 1, 2, 3 and 4 were begun with 1 drop followed by a daily increase of 1 drop until reaching 5 drops on the fth day. The maintenance dose of 5 drops from vial 4, corresponding to 0.5 g of the major grass allergen group 5, was administered 3 times a week until the end of July 2000. The grass mix included Dactylis glomerata, Festuca pratensis, Lolium perenne, Phleum pratense and Poa pratensis. In the build-up phase (30 days), the cumulative dose of major allergen was 1.88 g, whereas in the maintenance phase the cumulative dose/month of major allergen was 6 g. In the rst year, the cumulative dose was 67.88 g and in the second year 139.88 g of the major allergen in total (67.88 + (6 x 12 months)). Placebo: Identical glycerosaline phenolated solution. Conjunctival immediate allergen sensitivity Allergen: Grass mix Potential Conicts of interest: Not declared
Outcomes Notes
Risk of bias Bias Authors judgement Support for judgement Participants were randomised.
No details were provided. Investigators and participants were masked to treatment assignment for the duration of the study. Participants lost to follow-up or excluded were accounted for along with participants followed to designated follow-up periods. The specied outcomes in the methodology were reported in the results section. Small number of participants across each trial group.
Low risk
Other bias
Unclear risk
82
Characteristics of excluded studies [ordered by study ID]
Study Alvarez-Cuesta 2007 Amar 2009 Bahceciler 2001 Bahceciler 2005 Boquete 2006 Bordignon 2003 Brown 2001 Burastero 2008 Caffarelli 2000 Ciprandi 2007 Clavel 1996 Clavel 1998 Di Rienzo 2006 Didier 2009 Drachenberg 2001 Durham 2007 Durham 2010 Esch 2008 Grosclaude 2002 Guez 2000 Horak 2008 Horak 2009 Horak 2009a
Reason for exclusion Ocular outcomes were not evaluated Data not suitable for analysis Ocular outcomes were not evaluated Open trial, not placebo controlled Study designed to evaluate safety Not placebo controlled, other outcomes investigated Editorial Open trial, not placebo controlled Intervention classied as oral immunotherapy Open trial, not placebo controlled Data presented as full paper in 1998 Data not available Ocular outcomes were not evaluated Data already presented elsewhere Ocular outcomes were not evaluated Data was already presented in Dahl 2006b Data already presented elsewhere Data not available Study designed to evaluate safety Ocular outcomes were not evaluated Data were already presented in Didier 2007 Data already presented elsewhere No natural allergen exposure
83
(Continued)
Hordijk 1998 Horiguchi 2008a Horiguchi 2008b Ippoliti 2003 Kleine-Tebbe 2007 Lombardi 2005 Lue 2006 Maestrelli 2004 Malling 2009 Marcucci 2001 Marcucci 2003 Marcucci 2005a Marcucci 2005b Maria 2004 Mitsch 1996 Mungan 1999 Msges 2007 Nelson 1993 Niu 2006 Okubo 2008 Pajno 2000 Pajno 2003 Peter 2009 Potter 2007
Data not available Study single masked Not placebo controlled Ocular outcomes were not evaluated Review Double-intervention Ocular outcomes were not evaluated Subcutaneous immunotherapy Data already presented elsewhere Not placebo controlled Ocular outcomes were not evaluated Not placebo controlled Ocular outcomes were not evaluated Not placebo controlled Open study Single-masked study Data not available Data not available Data not available Data not available Ocular outcomes were not evaluated Double intervention Other outcomes were evaluated Data not available
84
(Continued)
Quirino 1996 Radu 2007 Roberta 2009a Roberta 2009b Rossi 2005 Rukhadze 2008 Sabbah 1994 Scadding 1986 Sieber 2009 Stelmach 2009 Stosovic 2008 Tari 1990 Tonnel 2004 Troise 2009 Tseng 2008 Ventura 2009 Wessner 2001 Worm 2006 Worm 2009 Yuksel 1999
Placebo controlled group not included Single-masked study Different study design Not placebo controlled Not randomised, not placebo controlled Not randomised, not placebo controlled Data not available Crossover design Not placebo controlled Differences in inclusion criteria Not placebo controlled Data not available Data not available Data not available Data not available Design differences Data not available Ocular outcomes were not evaluated Data already presented elsewhere Single-masked study
85
DATA AND ANALYSES
Comparison 1. Sublingual immunotherapy versus placebo
Outcome or subgroup title 1 Total ocular symptom scores 2 Itchy/Gritty eyes 3 Watery eyes 4 Red eyes 5 Swollen eyes 6 Eye drops 7 Combined symptom-medication scores 8 Conjunctival immediate allergen sensitivity 9 Total ocular symptom scores: Seasonal and perennial 9.1 Seasonal 9.2 Perennial 10 Total ocular symptom scores: Adults and children 10.1 Children 10.2 Adults 11 Total ocular symptom scores: Publication year 11.1 1994 - 1999 11.2 2000 - 2005 11.3 2006 - 2009 12 Total ocular symptom scores: Treatment > 12 months 12.1 12 months or less 12.2 13 months or more 13 Total ocular symptom scores: Fixed-effects model
No. of studies 36 28 21 20 2 13 3 4 36 30 6 36 9 27 36 11 10 15 36 26 10 36
No. of participants 3399 3020 2641 1211 132 1038 351 250 3399 3180 219 3399 857 2542 3399 451 575 2373 3399 2888 511 3399
Statistical method Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Fixed, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Fixed, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Random, 95% CI) Std. Mean Difference (IV, Fixed, 95% CI)
Effect size -0.41 [-0.53, -0.28] -0.31 [-0.42, -0.20] -0.23 [-0.34, -0.11] -0.33 [-0.45, -0.22] -0.23 [-1.19, 0.72] -0.10 [-0.22, 0.03] -0.21 [-0.55, 0.13] 0.35 [0.00, 0.69] -0.40 [-0.52, -0.28] -0.38 [-0.50, -0.25] -0.52 [-1.05, 0.01] -0.40 [-0.53, -0.28] -0.27 [-0.46, -0.07] -0.48 [-0.63, -0.32] -0.40 [-0.52, -0.28] -0.65 [-0.98, -0.33] -0.43 [-0.73, -0.13] -0.31 [-0.45, -0.17] -0.40 [-0.52, -0.28] -0.40 [-0.53, -0.27] -0.43 [-0.76, -0.10] -0.37 [-0.43, -0.30]
86
Analysis 1.1. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 1 Total ocular symptom scores.
Review: Sublingual immunotherapy for treating allergic conjunctivitis
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 1 Total ocular symptom scores
Study or subgroup
Sublingual Immunotherapy N Mean(SD) 1.3 (0.3) 12.7 (4.6) 0.7 (0.48) 27.2 (12.6) 5.76 (0.9)
Placebo N 16 10 10 15 19 16 Mean(SD) 2.1 (0.5) 28 (11.1) 1.9 (0.82) 45.3 (16.8) 7 (1.33) 58.29 (41.21)
Std. Mean Difference IV,Random,95% CI
Weight
Feliziani 1995 Passalacqua 1998 Ariano 2001 Passalacqua 1999 Mortemousque 2003 Palma-Carlos 2006 Panzner 2008 Casanovas 1994 Troise 1995 Khinchi 2004 Cao 2007 Purello-D Ambrosio 1999 Dahl 2006b Voltolini 2001 Wahn 2009 Dubakiene 2003 Sanchez-Palacios 2001 Andre 2003 Vourdas 1998 Didier 2007 Pradalier 1999 de Blay 2007 Bufe 2008 Valovirta 2006 Horak 1998
18 10 10 15 26
1.6 % 1.1 % 1.1 % 1.7 % 2.2 % 1.9 % 2.0 % 1.0 % 1.9 % 2.1 % 2.9 % 1.9 % 5.2 % 1.9 % 4.7 % 3.6 % 2.3 % 3.0 % 2.9 % 4.7 % 3.9 % 3.6 % 4.6 % 3.0 % 2.3 %
-4 -2 0 2 4
-1.92 [ -2.75, -1.09 ] -1.72 [ -2.78, -0.66 ] -1.71 [ -2.77, -0.65 ] -1.19 [ -1.97, -0.40 ] -1.11 [ -1.75, -0.47 ] -1.00 [ -1.73, -0.27 ] -0.91 [ -1.62, -0.20 ] -0.85 [ -1.94, 0.24 ] -0.78 [ -1.51, -0.04 ] -0.66 [ -1.32, 0.01 ] -0.61 [ -1.11, -0.11 ] -0.56 [ -1.30, 0.17 ] -0.56 [ -0.73, -0.40 ] -0.54 [ -1.27, 0.19 ] -0.51 [ -0.76, -0.27 ] -0.50 [ -0.90, -0.10 ] -0.46 [ -1.09, 0.16 ] -0.44 [ -0.92, 0.04 ] -0.38 [ -0.88, 0.11 ] -0.38 [ -0.62, -0.15 ] -0.38 [ -0.73, -0.02 ] -0.33 [ -0.72, 0.05 ] -0.30 [ -0.56, -0.05 ] -0.28 [ -0.77, 0.21 ] -0.23 [ -0.85, 0.38 ]
17 22.85 (27.02) 20 9 15 18 29 14 282 15 131 47 20 26 60.2 (81.25) 1.29 (0.73) 43 (50) 0.87 (0.576) 1.66 (1.03) 158 (174) 0.7 (0.6) 34.6 (39) 0.77 (1.016) 0.24 (0.27) 2 (2) 1.11 (0.91)
15 185.67 (183.85) 6 16 19 37 16 286 15 135 53 20 48 31 148 61 51 121 33 20 2.5 (1.96) 79 (40) 1.32 (0.75) 2.43 (1.39) 268 (202) 1.1 (0.8) 68 (75) 1.34 (1.194) 0.41 (0.39) 3.5 (4) 1.69 (1.48) 0.56 (1.259) 1.4 (1.24) 1.55 (1.53) 11.18 (10.82) 1.23 (1.14) 1.1 (0.9) 2.9 (4.12)
33 0.199 (0.466) 136 62 53 117 32 21 0.95 (1.1) 1.06 (1.02) 7.79 (9.28) 0.91 (0.95) 0.8 (1.2) 2 (3.46)
Favours SLIT
Favours Placebo
(Continued . . . )
87
(. . .
Study or subgroup Sublingual Immunotherapy N Bowen 2004 La Rosa 1999 Dahl 2006a Ott 2008 Durham 2006 Vervloet 2007 Moreno-Ancillo 2007 Hirsch 1997 Rolinck-Werninghaus 2004 Smith 2004 Aydogan 2007 27 16 61 123 141 22 51 15 39 45 9 Mean(SD) 1.96 (1.9) 0.23 (0.445) 0.75 (0.78) 1.28 (1.77) 0.74 (0.78) 1.14 (1.14) 0.48 (0.39) 0.36 (0.69) 6.83 (13.63) 1.09 (1.224) 0.22 (0.43) Placebo N 29 17 32 60 136 21 49 15 38 51 9 Mean(SD) 2.38 (1.92) 0.35 (0.629) 0.88 (0.68) 1.51 (1.93) 0.81 (0.75) 1.24 (1.4) 0.46 (0.31) 0.31 (0.62) 5.15 (9.81) 0.86 (0.748) 0.01 (0.02) Std. Mean Difference IV,Random,95% CI 2.8 % 2.0 % 3.4 % 4.2 % 4.7 % 2.4 % 3.6 % 1.9 % 3.2 % 3.5 % 1.3 % Weight
Continued) Std. Mean Difference IV,Random,95% CI -0.22 [ -0.74, 0.31 ] -0.21 [ -0.90, 0.47 ] -0.17 [ -0.60, 0.26 ] -0.13 [ -0.43, 0.18 ] -0.09 [ -0.33, 0.14 ] -0.08 [ -0.68, 0.52 ] 0.06 [ -0.34, 0.45 ] 0.07 [ -0.64, 0.79 ] 0.14 [ -0.31, 0.59 ] 0.23 [ -0.18, 0.63 ] 0.66 [ -0.30, 1.61 ]
Total (95% CI)

Test for overall effect: Z = 6.53 (P < 0.00001)
1725
1674
100.0 % -0.41 [ -0.53, -0.28 ]
Heterogeneity: Tau2 = 0.07; Chi2 = 85.79, df = 35 (P<0.00001); I2 =59%
-4
-2
Favours SLIT
Favours Placebo
88
Analysis 1.2. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 2 Itchy/Gritty eyes.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 2 Itchy/Gritty eyes
Study or subgroup
Sublingual Immunotherapy N Mean(SD) 0.5 (0.2) 20.7 (24.31) 0.72 (0.45) 20 (23) 16.8 (6) 16.4 (20) 2.2 (1) 70 (80) 0.51 (0.595) 0.46 (0.38) 0.56 (0.61) 0.81 (0.68) 0.77 (0.97) 0.51 (0.46) 0.1 (0.23) 0.47 (0.44) 0.48 (0.44) 0.11 (0.199) 0.82 (0.77) 0.96 (1.38) 0.48 (0.44)
Placebo N 16 Mean(SD) 0.9 (0.4)
Weight
Feliziani 1995 Panzner 2008 Cao 2007 Troise 1995 Passalacqua 1999 Voltolini 2001 Sanchez-Palacios 2001 Purello-D Ambrosio 1999 Wahn 2009 Dahl 2006b Didier 2007 Ott 2008 de Blay 2007 Andre 2003 Vourdas 1998 Pradalier 1999 Dahl 2006a La Rosa 1999 Bowen 2004 Horak 1998 Durham 2006 Dubakiene 2003 Rder 2007 Rolinck-Werninghaus 2004 Smith 2004 Vervloet 2007
18 20 29 15 15 15 20 14 131 282 136 123 53 26 33 62 61 16 27 21 141
1.8 % 1.9 % 3.1 % 1.8 % 1.8 % 1.8 % 2.3 % 1.8 % 6.4 % 7.6 % 6.5 % 5.3 % 4.3 % 3.4 % 3.3 % 4.7 % 3.9 % 2.0 % 3.0 % 2.4 % 6.5 % 4.3 % 5.5 % 3.7 % 4.2 % 2.5 %
-4 -2 0 2 4
-1.26 [ -2.00, -0.51 ] -0.97 [ -1.68, -0.26 ] -0.94 [ -1.46, -0.43 ] -0.74 [ -1.47, -0.01 ] -0.66 [ -1.39, 0.08 ] -0.62 [ -1.36, 0.11 ] -0.62 [ -1.26, 0.02 ] -0.54 [ -1.27, 0.19 ] -0.52 [ -0.77, -0.28 ] -0.46 [ -0.62, -0.29 ] -0.36 [ -0.60, -0.13 ] -0.34 [ -0.66, -0.03 ] -0.34 [ -0.72, 0.05 ] -0.31 [ -0.79, 0.17 ] -0.31 [ -0.80, 0.18 ] -0.30 [ -0.66, 0.06 ] -0.29 [ -0.72, 0.14 ] -0.28 [ -0.97, 0.40 ] -0.23 [ -0.76, 0.29 ] -0.23 [ -0.85, 0.38 ] -0.18 [ -0.41, 0.06 ] -0.16 [ -0.55, 0.24 ] -0.02 [ -0.33, 0.28 ] 0.06 [ -0.39, 0.50 ] 0.11 [ -0.29, 0.51 ] 0.12 [ -0.48, 0.72 ]
15 57.2 (48.73) 37 16 15 15 20 16 1.32 (0.74) 37 (22) 22 (9.1) 32 (28) 3.2 (2) 121 (101)
135 0.85 (0.699) 286 148 60 50 48 0.66 (0.49) 0.8 (0.706) 1.04 (0.63) 1.12 (1.1) 0.67 (0.53)
31 0.21 (0.457) 61 32 17 29 20 136 0.62 (0.55) 0.61 (0.47) 0.22 (0.49) 0.99 (0.67) 1.32 (1.65) 0.56 (0.46)
47 0.096 (0.336) 91 39 0.65 (0.5) 2.66 (4.54)
53 0.16 (0.485) 77 38 51 21 0.66 (0.4) 2.38 (5.07) 0.5 (0.349) 0.37 (0.5)
46 0.554 (0.541) 22 0.43 (0.47)
Favours SLIT
Favours control
(Continued . . . )
89
Study or subgroup
Sublingual Immunotherapy N Mean(SD) 0.4 (0.3) 0.28 (0.48)
Placebo N 28 9 Mean(SD) 0.3 (0.3) 0 (0.013)
Weight
(. . . Continued) Std. Mean Difference

IV,Random,95% CI 0.33 [ -0.20, 0.86 ] 0.77 [ -0.19, 1.74 ]
Passalacqua 2006 Aydogan 2007
28 9
3.0 % 1.1 %
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
Favours SLIT
Favours control
Analysis 1.3. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 3 Watery eyes.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 3 Watery eyes
Study or subgroup
Sublingual Immunotherapy N Mean(SD) 13.8 (22.08) 0.25 (0.24) 0.22 (0.28) 0.26 (0.493) 0.27 (0.32) 0.39 (0.554) 2.3 (3) 0.24 (0.36) 0.57 (0.58)
Placebo N Mean(SD)
Weight
Panzner 2008 Andre 2003 Dahl 2006b Wahn 2009 Pradalier 1999 Didier 2007 Sanchez-Palacios 2001 Vervloet 2007 Bowen 2004 Dubakiene 2003 Cao 2007 Horak 1998 Vourdas 1998 Ott 2008
20 26 282 131 62 136 20 22 27
15 44.13 (49.55) 48 286 135 61 148 20 21 29 53 37 20 31 60 0.49 (0.49) 0.39 (0.4) 0.49 (0.574) 0.43 (0.54) 0.59 (0.627) 3 (1) 0.36 (0.52) 0.73 (0.65) 0.09 (0.373) 0.81 (0.65) 0.8 (1.43) 0.12 (0.412) 0.49 (0.58)
-4 -2 0 2 4
2.2 % 3.8 % 10.3 % 8.2 % 5.7 % 8.4 % 2.6 % 2.8 % 3.4 % 5.0 % 3.8 % 2.7 % 3.8 % 6.6 %
-0.81 [ -1.51, -0.12 ] -0.56 [ -1.05, -0.08 ] -0.49 [ -0.66, -0.32 ] -0.43 [ -0.67, -0.19 ] -0.36 [ -0.72, 0.00 ] -0.34 [ -0.57, -0.10 ] -0.31 [ -0.93, 0.32 ] -0.26 [ -0.87, 0.34 ] -0.26 [ -0.78, 0.27 ] -0.25 [ -0.64, 0.14 ] -0.24 [ -0.72, 0.25 ] -0.22 [ -0.84, 0.39 ] -0.20 [ -0.69, 0.29 ] -0.19 [ -0.50, 0.12 ]
47 0.014 (0.132) 29 21 0.66 (0.6) 0.51 (1.11)
33 0.061 (0.163) 123 0.37 (0.67)
Favours SLIT
Favours Placebo
(Continued . . . )
90
Study or subgroup
Sublingual Immunotherapy N Mean(SD) 0.42 (0.75) 0.04 (0.082) 0.26 (0.39) 0.25 (0.38) 2.04 (4.98) 0.27 (0.367) 0.15 (0.32)
Placebo N 50 17 32 136 38 51 9 Mean(SD) 0.56 (0.84) 0.05 (0.112) 0.27 (0.31) 0.25 (0.34) 1.08 (2.77) 0.19 (0.214) 0.02 (0.04)
Weight
(. . . Continued) Std. Mean Difference

IV,Random,95% CI -0.17 [ -0.56, 0.21 ] -0.10 [ -0.78, 0.58 ] -0.03 [ -0.46, 0.40 ] 0.0 [ -0.24, 0.24 ] 0.24 [ -0.21, 0.68 ] 0.27 [ -0.13, 0.67 ] 0.53 [ -0.41, 1.47 ]
de Blay 2007 La Rosa 1999 Dahl 2006a Durham 2006 Rolinck-Werninghaus 2004 Smith 2004 Aydogan 2007
53 16 61 141 39 46 9
5.2 % 2.3 % 4.5 % 8.4 % 4.3 % 4.9 % 1.3 %
Total (95% CI)

Test for overall effect: Z = 3.95 (P = 0.000077)
1344
1297
100.0 % -0.23 [ -0.34, -0.11 ]
-4
-2
Favours SLIT
Favours Placebo
Analysis 1.4. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 4 Red eyes.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 4 Red eyes
Study or subgroup
Sublingual Immunotherapy N Mean(SD) 12 (7.1) 16.9 (31.29) 2 (1) 23 (25) 0.8 (0.5) 18.2 (22)
Placebo N 15 Mean(SD) 26 (12.1)
Std. Mean Difference IV,Fixed,95% CI
Weight
Passalacqua 1999 Panzner 2008 Sanchez-Palacios 2001 Troise 1995 Feliziani 1995 Voltolini 2001 Vourdas 1998 Purello-D Ambrosio 1999 Ott 2008
15 20 20 15 18 15
2.1 % 2.7 % 3.2 % 2.5 % 2.8 % 2.5 % 5.4 % 2.5 % 13.7 %

-4 -2 0 2 4
-1.37 [ -2.18, -0.57 ] -0.82 [ -1.52, -0.12 ] -0.76 [ -1.41, -0.12 ] -0.76 [ -1.49, -0.02 ] -0.65 [ -1.34, 0.04 ] -0.56 [ -1.29, 0.17 ] -0.50 [ -0.99, 0.00 ] -0.48 [ -1.21, 0.25 ] -0.47 [ -0.78, -0.16 ]
15 51.47 (51.66) 20 16 16 15 31 16 60 4.8 (5) 42 (24) 1.2 (0.7) 34 (32) 0.23 (0.526) 147 (137) 0.71 (0.64)
33 0.039 (0.125) 14 123 88 (95) 0.4 (0.66)
Favours SLIT
Favours Placebo
(Continued . . . )
91
(. . .
Study or subgroup Sublingual Immunotherapy N Andre 2003 Pradalier 1999 Cao 2007 Dubakiene 2003 Horak 1998 de Blay 2007 Bowen 2004 Vervloet 2007 La Rosa 1999 Rolinck-Werninghaus 2004 Aydogan 2007 26 62 29 Mean(SD) 0.35 (0.36) 0.33 (0.41) 0.24 (0.43) Placebo N 48 61 37 53 20 50 29 21 17 38 9 Mean(SD) 0.52 (0.52) 0.5 (0.53) 0.38 (0.48) 0.13 (0.451) 0.78 (1.37) 0.54 (0.84) 0.66 (0.7) 0.5 (0.63) 0.08 (0.175) 1.69 (2.56) 0.02 (0.04) Std. Mean Difference IV,Fixed,95% CI 5.8 % 10.5 % 5.6 % 8.6 % 3.5 % 8.9 % 4.9 % 3.7 % 2.9 % 6.7 % 1.5 % Weight
Continued) IV,Fixed,95% CI
Std. Mean Difference
-0.36 [ -0.84, 0.12 ] -0.36 [ -0.71, 0.00 ] -0.30 [ -0.79, 0.19 ] -0.22 [ -0.62, 0.17 ] -0.20 [ -0.81, 0.42 ] -0.14 [ -0.53, 0.24 ] -0.13 [ -0.66, 0.39 ] -0.05 [ -0.65, 0.55 ] 0.05 [ -0.63, 0.73 ] 0.12 [ -0.33, 0.57 ] 0.70 [ -0.26, 1.66 ]
47 0.049 (0.256) 21 53 27 22 16 39 9 0.53 (1.13) 0.43 (0.69) 0.57 (0.64) 0.47 (0.53) 0.09 (0.227) 2.13 (4.45) 0.3 (0.54)
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
Favours SLIT
Favours Placebo
Analysis 1.5. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 5 Swollen eyes.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 5 Swollen eyes
Study or subgroup
Sublingual Immunotherapy N Mean(SD) 8.8 (15.94)
Placebo N Mean(SD)
Weight
Panzner 2008 Smith 2004
20
15 32.87 (43.21) 51 0.17 (0.27)
45.6 % 54.4 %
-0.77 [ -1.46, -0.07 ] 0.21 [ -0.19, 0.61 ]
46 0.246 (0.418)
Total (95% CI)

66
66
100.0 %
-0.23 [ -1.19, 0.72 ]
-2
-1
Favours SLIT
Favours Placebo
92
Analysis 1.6. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 6 Eye drops.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 6 Eye drops
Study or subgroup
Sublingual Immunotherapy N Mean(SD) 2.4 (2) 4.2 (5) 2.07 (1.46) 6 (7) 0.35 (0.8)
Placebo N 20 15 37 16 50 Mean(SD) 5 (3) 7.6 (6.5) 2.97 (2.17) 8 (6.6) 0.54 (0.85)
Weight
Sanchez-Palacios 2001 Voltolini 2001 Cao 2007 Troise 1995 de Blay 2007 Andre 2003 Dahl 2006a Pradalier 1999 Dubakiene 2003 Ott 2008 Moreno-Ancillo 2007 Khinchi 2004 Vervloet 2007
20 15 29 15 53
3.5 % 2.9 % 6.4 % 3.1 % 10.3 % 8.9 % 8.4 % 12.4 % 10.0 % 16.2 % 10.0 % 3.7 % 4.3 %
-1.00 [ -1.66, -0.34 ] -0.57 [ -1.30, 0.16 ] -0.47 [ -0.96, 0.02 ] -0.29 [ -1.00, 0.42 ] -0.23 [ -0.62, 0.16 ] -0.22 [ -0.64, 0.20 ] -0.07 [ -0.50, 0.35 ] -0.06 [ -0.42, 0.29 ] -0.03 [ -0.43, 0.36 ] 0.14 [ -0.16, 0.45 ] 0.14 [ -0.25, 0.54 ] 0.16 [ -0.49, 0.80 ] 0.28 [ -0.32, 0.89 ]
44 0.68 (1.895) 61 0.79 (1.72)
45 1.07 (1.604) 32 0.92 (1.78)
62 0.59 (1.221) 47 0.131 (0.423) 123 51 0.97 (5.36) 0.49 (0.5)
61 0.68 (1.594) 53 0.15 (0.373) 60 49 0.33 (0.65) 0.42 (0.46)
18 1.99 (2.981) 22 0.35 (0.68)
19 1.57 (2.148) 21 0.17 (0.55)
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
Favours SLIT
Favours Placebo
93
Analysis 1.7. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 7 Combined symptommedication scores.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 7 Combined symptom-medication scores
Study or subgroup
Sublingual Immunotherapy N Mean(SD)
Placebo N Mean(SD)
Weight
Pfaar 2008 Bufe 2004 Moreno-Ancillo 2007
42 91.8 (103.6) 83 51 0.5 (0.44) 0.73 (0.61)
48 151.1 (113) 78 49 0.6 (0.44) 0.67 (0.45)
29.9 % 38.1 % 32.0 %
-0.54 [ -0.96, -0.12 ] -0.23 [ -0.54, 0.08 ] 0.11 [ -0.28, 0.50 ]
Total (95% CI)

176
175
100.0 %
-0.21 [ -0.55, 0.13 ]
-4
-2
Favours SLIT
Favours Placebo
Analysis 1.8. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 8 Conjunctival immediate allergen sensitivity.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 8 Conjunctival immediate allergen sensitivity
Study or subgroup
Sublingual Immunotherapy N Mean(SD) 34.97 (32.26) 4.76 (1.32) 6.5 (9.16)
Placebo N Mean(SD)
Weight
Smith 2004 Rolinck-Werninghaus 2004 Horak 1998 Mortemousque 2003
45 38 21
46 33.26 (30.55) 35 20 4.54 (1.22) 2.7 (2.38)
31.7 % 28.4 % 19.8 % 20.1 %
0.05 [ -0.36, 0.47 ] 0.17 [ -0.29, 0.63 ] 0.55 [ -0.07, 1.18 ] 0.85 [ 0.23, 1.47 ]
26 30.861 (27.871)
19 11.65 (10.164)
Total (95% CI)

130
120
100.0 %
0.35 [ 0.00, 0.69 ]
-4
-2
Favours Placebo
Favours SLIT
94
Analysis 1.9. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 9 Total ocular symptom scores: Seasonal and perennial.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 9 Total ocular symptom scores: Seasonal and perennial
Study or subgroup
Placebo N Mean(SD)
Weight
1 Seasonal Feliziani 1995 Ariano 2001 Passalacqua 1999 Palma-Carlos 2006 Panzner 2008 Casanovas 1994 Troise 1995 Khinchi 2004 Purello-D Ambrosio 1999 Dahl 2006b Voltolini 2001 Wahn 2009 Dubakiene 2003 Andre 2003 Vourdas 1998 Didier 2007 Pradalier 1999 de Blay 2007 Valovirta 2006 Horak 1998 Bowen 2004 La Rosa 1999 Bufe 2008 Dahl 2006a 18 10 15 1.3 (0.3) 0.7 (0.48) 27.2 (12.6) 16 10 15 16 2.1 (0.5) 1.9 (0.82) 45.3 (16.8) 58.29 (41.21) 1.6 % 1.1 % 1.7 % 1.9 % 2.0 % 1.0 % 1.9 % 2.1 % 1.9 % 5.1 % 1.9 % 4.6 % 3.5 % 3.0 % 3.0 % 4.7 % 3.8 % 3.6 % 3.0 % 2.3 % 2.8 % 2.1 % 4.6 % 3.4 %
-4 -2 0 2 4
-1.92 [ -2.75, -1.09 ] -1.71 [ -2.77, -0.65 ] -1.19 [ -1.97, -0.40 ] -1.00 [ -1.73, -0.27 ] -0.91 [ -1.62, -0.20 ] -0.85 [ -1.94, 0.24 ] -0.78 [ -1.51, -0.04 ] -0.66 [ -1.32, 0.01 ] -0.56 [ -1.30, 0.17 ] -0.56 [ -0.73, -0.40 ] -0.54 [ -1.27, 0.19 ] -0.51 [ -0.76, -0.27 ] -0.50 [ -0.90, -0.10 ] -0.44 [ -0.92, 0.04 ] -0.38 [ -0.88, 0.11 ] -0.38 [ -0.62, -0.15 ] -0.38 [ -0.73, -0.02 ] -0.33 [ -0.72, 0.05 ] -0.28 [ -0.77, 0.21 ] -0.23 [ -0.85, 0.38 ] -0.22 [ -0.74, 0.31 ] -0.21 [ -0.90, 0.47 ] -0.17 [ -0.43, 0.08 ] -0.17 [ -0.60, 0.26 ]
17 22.85 (27.02) 20 9 15 18 14 282 15 131 47 26 60.2 (81.25) 1.29 (0.73) 43 (50) 0.87 (0.576) 158 (174) 0.7 (0.6) 34.6 (39) 0.77 (1.016) 0.24 (0.27) 1.11 (0.91)
15 185.67 (183.85) 6 16 19 16 286 15 135 53 48 31 148 61 51 33 20 29 17 121 32 2.5 (1.96) 79 (40) 1.32 (0.75) 268 (202) 1.1 (0.8) 68 (75) 1.34 (1.194) 0.41 (0.39) 1.69 (1.48) 0.56 (1.259) 1.4 (1.24) 1.55 (1.53) 11.18 (10.82) 1.1 (0.9) 2.9 (4.12) 2.38 (1.92) 0.35 (0.629) 0.79 (0.73) 0.88 (0.68)
33 0.199 (0.466) 136 62 53 32 21 27 16 117 61 0.95 (1.1) 1.06 (1.02) 7.79 (9.28) 0.8 (1.2) 2 (3.46) 1.96 (1.9) 0.23 (0.445) 0.66 (0.76) 0.75 (0.78)
Favours SLIT
Favours Placebo
(Continued . . . )
95
(. . .
Study or subgroup Sublingual Immunotherapy N Ott 2008 Durham 2006 Vervloet 2007 Moreno-Ancillo 2007 Rolinck-Werninghaus 2004 Smith 2004 123 141 22 51 39 45 Mean(SD) 1.28 (1.77) 0.74 (0.78) 1.14 (1.14) 0.48 (0.39) 6.83 (13.63) 1.09 (1.224) Placebo N 60 136 21 49 38 51 Mean(SD) 1.51 (1.93) 0.81 (0.75) 1.24 (1.4) 0.46 (0.31) 5.15 (9.81) 0.86 (0.748) Std. Mean Difference IV,Random,95% CI 4.2 % 4.7 % 2.4 % 3.6 % 3.2 % 3.5 % Weight
Continued) Std. Mean Difference IV,Random,95% CI -0.13 [ -0.43, 0.18 ] -0.09 [ -0.33, 0.14 ] -0.08 [ -0.68, 0.52 ] 0.06 [ -0.34, 0.45 ] 0.14 [ -0.31, 0.59 ] 0.23 [ -0.18, 0.63 ]
Subtotal (95% CI)

Test for overall effect: Z = 5.98 (P < 0.00001) 2 Perennial Passalacqua 1998 Mortemousque 2003 Cao 2007 Sanchez-Palacios 2001 Hirsch 1997 Aydogan 2007
1616
1564
88.2 % -0.38 [ -0.50, -0.25 ]
10 26 29 20 15 9
12.7 (4.6) 5.76 (0.9) 1.66 (1.03) 2 (2) 0.36 (0.69) 0.22 (0.43)
10 19 37 20 15 9
28 (11.1) 7 (1.33) 2.43 (1.39) 3.5 (4) 0.31 (0.62) 0.01 (0.02)
1.1 % 2.2 % 2.9 % 2.3 % 1.9 % 1.3 %
-1.72 [ -2.78, -0.66 ] -1.11 [ -1.75, -0.47 ] -0.61 [ -1.11, -0.11 ] -0.46 [ -1.09, 0.16 ] 0.07 [ -0.64, 0.79 ] 0.66 [ -0.30, 1.61 ]
Subtotal (95% CI)

109
110
11.8 %
-0.52 [ -1.05, 0.01 ]
Total (95% CI)

1725
1674
100.0 % -0.40 [ -0.52, -0.28 ]
-4
-2
Favours SLIT
Favours Placebo
96
Analysis 1.10. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 10 Total ocular symptom scores: Adults and children.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 10 Total ocular symptom scores: Adults and children
Study or subgroup
Placebo N Mean(SD)
Weight
1 Children Cao 2007 Wahn 2009 Vourdas 1998 Bufe 2008 Valovirta 2006 La Rosa 1999 Hirsch 1997 Rolinck-Werninghaus 2004 Aydogan 2007 29 131 1.66 (1.03) 0.77 (1.016) 37 135 31 121 33 17 15 38 9 2.43 (1.39) 1.34 (1.194) 0.56 (1.259) 1.23 (1.14) 1.1 (0.9) 0.79 (0.73) 0.31 (0.62) 5.15 (9.81) 0.01 (0.02) 2.9 % 4.7 % 2.9 % 4.6 % 3.0 % 2.0 % 1.9 % 3.2 % 1.3 % -0.61 [ -1.11, -0.11 ] -0.51 [ -0.76, -0.27 ] -0.38 [ -0.88, 0.11 ] -0.30 [ -0.56, -0.05 ] -0.28 [ -0.77, 0.21 ] -0.17 [ -0.85, 0.51 ] 0.07 [ -0.64, 0.79 ] 0.14 [ -0.31, 0.59 ] 0.66 [ -0.30, 1.61 ]
33 0.199 (0.466) 117 32 16 15 39 9 0.91 (0.95) 0.8 (1.2) 0.66 (0.76) 0.36 (0.69) 6.83 (13.63) 0.22 (0.43)
Subtotal (95% CI)

Test for overall effect: Z = 2.69 (P = 0.0071) 2 Adults Feliziani 1995 Passalacqua 1998 Ariano 2001 Passalacqua 1999 Mortemousque 2003 Palma-Carlos 2006 Panzner 2008 Casanovas 1994 Troise 1995 Khinchi 2004 Purello-D Ambrosio 1999 Dahl 2006b
421
436
26.6 % -0.27 [ -0.46, -0.07 ]
18 10 10 15 26
1.3 (0.3) 12.7 (4.6) 0.7 (0.48) 27.2 (12.6) 5.76 (0.9)
16 10 10 15 19 16
2.1 (0.5) 28 (11.1) 1.9 (0.82) 45.3 (16.8) 7 (1.33) 58.29 (41.21)
1.6 % 1.1 % 1.1 % 1.7 % 2.2 % 1.9 % 2.0 % 1.0 % 1.9 % 2.1 % 1.9 % 5.2 %
-4 -2 0 2 4
-1.92 [ -2.75, -1.09 ] -1.72 [ -2.78, -0.66 ] -1.71 [ -2.77, -0.65 ] -1.19 [ -1.97, -0.40 ] -1.11 [ -1.75, -0.47 ] -1.00 [ -1.73, -0.27 ] -0.91 [ -1.62, -0.20 ] -0.85 [ -1.94, 0.24 ] -0.78 [ -1.51, -0.04 ] -0.66 [ -1.32, 0.01 ] -0.56 [ -1.30, 0.17 ] -0.56 [ -0.73, -0.40 ]
17 22.85 (27.02) 20 9 15 18 14 282 60.2 (81.25) 1.29 (0.73) 43 (50) 0.87 (0.576) 158 (174) 0.7 (0.6)
15 185.67 (183.85) 6 16 19 16 286 2.5 (1.96) 79 (40) 1.32 (0.75) 268 (202) 1.1 (0.8)
Favours SLIT
Favours Placebo
(Continued . . . )
97
(. . .
Study or subgroup Sublingual Immunotherapy N Voltolini 2001 Dubakiene 2003 Sanchez-Palacios 2001 Andre 2003 Didier 2007 Pradalier 1999 de Blay 2007 Horak 1998 Bowen 2004 Dahl 2006a Ott 2008 Durham 2006 Vervloet 2007 Moreno-Ancillo 2007 Smith 2004 15 47 20 26 136 62 53 21 27 61 123 141 22 51 45 Mean(SD) 34.6 (39) 0.24 (0.27) 2 (2) 1.11 (0.91) 0.95 (1.1) 1.06 (1.02) 7.79 (9.28) 2 (3.46) 1.96 (1.9) 0.75 (0.78) 1.28 (1.77) 0.74 (0.78) 1.14 (1.14) 0.48 (0.39) 1.09 (1.224) Placebo N 15 53 20 48 148 61 51 20 29 32 60 136 21 49 51 Mean(SD) 68 (75) 0.41 (0.39) 3.5 (4) 1.69 (1.48) 1.4 (1.24) 1.55 (1.53) 11.18 (10.82) 2.9 (4.12) 2.38 (1.92) 0.88 (0.68) 1.51 (1.93) 0.81 (0.75) 1.24 (1.4) 0.46 (0.31) 0.86 (0.748) Std. Mean Difference IV,Random,95% CI 1.9 % 3.6 % 2.3 % 3.0 % 4.7 % 3.9 % 3.6 % 2.3 % 2.8 % 3.4 % 4.2 % 4.7 % 2.4 % 3.6 % 3.5 % Weight
Continued) Std. Mean Difference IV,Random,95% CI -0.54 [ -1.27, 0.19 ] -0.50 [ -0.90, -0.10 ] -0.46 [ -1.09, 0.16 ] -0.44 [ -0.92, 0.04 ] -0.38 [ -0.62, -0.15 ] -0.38 [ -0.73, -0.02 ] -0.33 [ -0.72, 0.05 ] -0.23 [ -0.85, 0.38 ] -0.22 [ -0.74, 0.31 ] -0.17 [ -0.60, 0.26 ] -0.13 [ -0.43, 0.18 ] -0.09 [ -0.33, 0.14 ] -0.08 [ -0.68, 0.52 ] 0.06 [ -0.34, 0.45 ] 0.23 [ -0.18, 0.63 ]
Subtotal (95% CI)

1304
1238
73.4 % -0.48 [ -0.63, -0.32 ]
Total (95% CI)

1725
1674
100.0 % -0.40 [ -0.53, -0.28 ]
-4
-2
Favours SLIT
Favours Placebo
98
Analysis 1.11. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 11 Total ocular symptom scores: Publication year.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 11 Total ocular symptom scores: Publication year
Study or subgroup
Placebo N Mean(SD)
Weight
1 1994 - 1999 Feliziani 1995 Passalacqua 1998 Passalacqua 1999 Casanovas 1994 Troise 1995 Purello-D Ambrosio 1999 Vourdas 1998 Pradalier 1999 Horak 1998 La Rosa 1999 Hirsch 1997 18 10 15 9 15 14 1.3 (0.3) 12.7 (4.6) 27.2 (12.6) 1.29 (0.73) 43 (50) 158 (174) 16 10 15 6 16 16 31 61 20 17 15 2.1 (0.5) 28 (11.1) 45.3 (16.8) 2.5 (1.96) 79 (40) 268 (202) 0.56 (1.259) 1.55 (1.53) 2.9 (4.12) 0.35 (0.629) 0.31 (0.62) 1.6 % 1.1 % 1.7 % 1.0 % 1.9 % 1.9 % 3.0 % 3.8 % 2.3 % 2.1 % 1.9 % -1.92 [ -2.75, -1.09 ] -1.72 [ -2.78, -0.66 ] -1.19 [ -1.97, -0.40 ] -0.85 [ -1.94, 0.24 ] -0.78 [ -1.51, -0.04 ] -0.56 [ -1.30, 0.17 ] -0.38 [ -0.88, 0.11 ] -0.38 [ -0.73, -0.02 ] -0.23 [ -0.85, 0.38 ] -0.21 [ -0.90, 0.47 ] 0.07 [ -0.64, 0.79 ]
33 0.199 (0.466) 62 21 16 15 1.06 (1.02) 2 (3.46) 0.23 (0.445) 0.36 (0.69)
Subtotal (95% CI)

Test for overall effect: Z = 3.98 (P = 0.000069) 2 2000 - 2005 Ariano 2001 Mortemousque 2003 Khinchi 2004 Voltolini 2001 Dubakiene 2003 Sanchez-Palacios 2001 Andre 2003 Bowen 2004 Rolinck-Werninghaus 2004 Smith 2004
228
223
22.3 % -0.65 [ -0.98, -0.33 ]
10 26 18 15 47 20 26 27 39 45
0.7 (0.48) 5.76 (0.9) 0.87 (0.576) 34.6 (39) 0.24 (0.27) 2 (2) 1.11 (0.91) 1.96 (1.9) 6.83 (13.63) 1.09 (1.224)
10 19 19 15 53 20 48 29 38 51
1.9 (0.82) 7 (1.33) 1.32 (0.75) 68 (75) 0.41 (0.39) 3.5 (4) 1.69 (1.48) 2.38 (1.92) 5.15 (9.81) 0.86 (0.748)
-4 -2 0 2 4
1.1 % 2.2 % 2.1 % 1.9 % 3.5 % 2.3 % 3.0 % 2.8 % 3.2 % 3.5 %
-1.71 [ -2.77, -0.65 ] -1.11 [ -1.75, -0.47 ] -0.66 [ -1.32, 0.01 ] -0.54 [ -1.27, 0.19 ] -0.50 [ -0.90, -0.10 ] -0.46 [ -1.09, 0.16 ] -0.44 [ -0.92, 0.04 ] -0.22 [ -0.74, 0.31 ] 0.14 [ -0.31, 0.59 ] 0.23 [ -0.18, 0.63 ]
Favours SLIT
Favours Placebo
(Continued . . . )
99
(. . .
Study or subgroup Sublingual Immunotherapy N Mean(SD) Placebo N Mean(SD) Std. Mean Difference IV,Random,95% CI Weight
Continued) Std. Mean Difference IV,Random,95% CI
Subtotal (95% CI)

Test for overall effect: Z = 2.83 (P = 0.0047) 3 2006 - 2009 Palma-Carlos 2006 Panzner 2008 Cao 2007 Dahl 2006b Wahn 2009 Didier 2007 de Blay 2007 Valovirta 2006 Bufe 2008 Dahl 2006a Ott 2008 Durham 2006 Vervloet 2007 Moreno-Ancillo 2007 Aydogan 2007
273
302
25.8 % -0.43 [ -0.73, -0.13 ]
17 22.85 (27.02) 20 29 282 131 136 53 32 117 61 123 141 22 51 9 60.2 (81.25) 1.66 (1.03) 0.7 (0.6) 0.77 (1.016) 0.95 (1.1) 7.79 (9.28) 0.8 (1.2) 0.66 (0.76) 0.75 (0.78) 1.28 (1.77) 0.74 (0.78) 1.14 (1.14) 0.48 (0.39) 0.22 (0.43)
16
58.29 (41.21)
1.9 % 2.0 % 2.9 % 5.1 % 4.6 % 4.7 % 3.6 % 3.0 % 4.6 % 3.4 % 4.2 % 4.7 % 2.4 % 3.6 % 1.3 %
-1.00 [ -1.73, -0.27 ] -0.91 [ -1.62, -0.20 ] -0.61 [ -1.11, -0.11 ] -0.56 [ -0.73, -0.40 ] -0.51 [ -0.76, -0.27 ] -0.38 [ -0.62, -0.15 ] -0.33 [ -0.72, 0.05 ] -0.28 [ -0.77, 0.21 ] -0.17 [ -0.43, 0.08 ] -0.17 [ -0.60, 0.26 ] -0.13 [ -0.43, 0.18 ] -0.09 [ -0.33, 0.14 ] -0.08 [ -0.68, 0.52 ] 0.06 [ -0.34, 0.45 ] 0.66 [ -0.30, 1.61 ]
15 185.67 (183.85) 37 286 135 148 51 33 121 32 60 136 21 49 9 2.43 (1.39) 1.1 (0.8) 1.34 (1.194) 1.4 (1.24) 11.18 (10.82) 1.1 (0.9) 0.79 (0.73) 0.88 (0.68) 1.51 (1.93) 0.81 (0.75) 1.24 (1.4) 0.46 (0.31) 0.01 (0.02)
Subtotal (95% CI)

1224
1149
51.9 % -0.31 [ -0.45, -0.17 ]
Total (95% CI)

1725
1674
100.0 % -0.40 [ -0.52, -0.28 ]
-4
-2
Favours SLIT
Favours Placebo
100
Analysis 1.12. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 12 Total ocular symptom scores: Treatment > 12 months.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 12 Total ocular symptom scores: Treatment > 12 months
Study or subgroup
Placebo N Mean(SD)
Weight
1 12 months or less Feliziani 1995 Ariano 2001 Passalacqua 1999 Panzner 2008 Casanovas 1994 Troise 1995 Cao 2007 Purello-D Ambrosio 1999 Dahl 2006b Voltolini 2001 Wahn 2009 Dubakiene 2003 Sanchez-Palacios 2001 Andre 2003 Didier 2007 Pradalier 1999 de Blay 2007 Bowen 2004 Bufe 2008 Dahl 2006a Ott 2008 Durham 2006 Vervloet 2007 Moreno-Ancillo 2007 18 10 15 20 9 15 29 14 282 15 131 47 20 26 136 62 53 27 117 61 123 141 22 51 1.3 (0.3) 0.7 (0.48) 27.2 (12.6) 60.2 (81.25) 1.29 (0.73) 43 (50) 1.66 (1.03) 158 (174) 0.7 (0.6) 34.6 (39) 0.77 (1.016) 0.24 (0.27) 2 (2) 1.11 (0.91) 0.95 (1.1) 1.06 (1.02) 7.79 (9.28) 1.96 (1.9) 0.66 (0.76) 0.75 (0.78) 1.28 (1.77) 0.74 (0.78) 1.14 (1.14) 0.48 (0.39) 16 10 15 2.1 (0.5) 1.9 (0.82) 45.3 (16.8) 1.6 % 1.1 % 1.7 % 2.0 % 1.0 % 1.9 % 2.9 % 1.9 % 5.1 % 1.9 % 4.6 % 3.5 % 2.3 % 3.0 % 4.7 % 3.8 % 3.6 % 2.8 % 4.6 % 3.4 % 4.2 % 4.7 % 2.4 % 3.6 %
-4 -2 0 2 4
-1.92 [ -2.75, -1.09 ] -1.71 [ -2.77, -0.65 ] -1.19 [ -1.97, -0.40 ] -0.91 [ -1.62, -0.20 ] -0.85 [ -1.94, 0.24 ] -0.78 [ -1.51, -0.04 ] -0.61 [ -1.11, -0.11 ] -0.56 [ -1.30, 0.17 ] -0.56 [ -0.73, -0.40 ] -0.54 [ -1.27, 0.19 ] -0.51 [ -0.76, -0.27 ] -0.50 [ -0.90, -0.10 ] -0.46 [ -1.09, 0.16 ] -0.44 [ -0.92, 0.04 ] -0.38 [ -0.62, -0.15 ] -0.38 [ -0.73, -0.02 ] -0.33 [ -0.72, 0.05 ] -0.22 [ -0.74, 0.31 ] -0.17 [ -0.43, 0.08 ] -0.17 [ -0.60, 0.26 ] -0.13 [ -0.43, 0.18 ] -0.09 [ -0.33, 0.14 ] -0.08 [ -0.68, 0.52 ] 0.06 [ -0.34, 0.45 ]
15 185.67 (183.85) 6 16 37 16 286 15 135 53 20 48 148 61 51 29 121 32 60 136 21 49 2.5 (1.96) 79 (40) 2.43 (1.39) 268 (202) 1.1 (0.8) 68 (75) 1.34 (1.194) 0.41 (0.39) 3.5 (4) 1.69 (1.48) 1.4 (1.24) 1.55 (1.53) 11.18 (10.82) 2.38 (1.92) 0.79 (0.73) 0.88 (0.68) 1.51 (1.93) 0.81 (0.75) 1.24 (1.4) 0.46 (0.31)
Favours SLIT
Favours Placebo
(Continued . . . )
101
(. . .
Study or subgroup Sublingual Immunotherapy N Hirsch 1997 Aydogan 2007 15 9 Mean(SD) 0.36 (0.69) 0.22 (0.43) Placebo N 15 9 Mean(SD) 0.31 (0.62) 0.01 (0.02) Std. Mean Difference IV,Random,95% CI 1.9 % 1.3 % Weight
Continued) Std. Mean Difference IV,Random,95% CI 0.07 [ -0.64, 0.79 ] 0.66 [ -0.30, 1.61 ]
Subtotal (95% CI)

Test for overall effect: Z = 5.97 (P < 0.00001) 2 13 months or more Passalacqua 1998 Mortemousque 2003 Palma-Carlos 2006 Khinchi 2004 Vourdas 1998 Valovirta 2006 Horak 1998 La Rosa 1999 Rolinck-Werninghaus 2004 Smith 2004
1468
1420
75.5 % -0.40 [ -0.53, -0.27 ]
10 26
12.7 (4.6) 5.76 (0.9)
10 19 16 19 31 33 20 17 38 51
28 (11.1) 7 (1.33) 58.29 (41.21) 1.32 (0.75) 0.56 (1.259) 1.1 (0.9) 2.9 (4.12) 0.35 (0.629) 5.15 (9.81) 0.86 (0.748)
1.1 % 2.2 % 1.9 % 2.1 % 3.0 % 3.0 % 2.3 % 2.1 % 3.2 % 3.5 %
-1.72 [ -2.78, -0.66 ] -1.11 [ -1.75, -0.47 ] -1.00 [ -1.73, -0.27 ] -0.66 [ -1.32, 0.01 ] -0.38 [ -0.88, 0.11 ] -0.28 [ -0.77, 0.21 ] -0.23 [ -0.85, 0.38 ] -0.21 [ -0.90, 0.47 ] 0.14 [ -0.31, 0.59 ] 0.23 [ -0.18, 0.63 ]
17 22.85 (27.02) 18 0.87 (0.576)
33 0.199 (0.466) 32 21 16 39 45 0.8 (1.2) 2 (3.46) 0.23 (0.445) 6.83 (13.63) 1.09 (1.224)
Subtotal (95% CI)

257
254
24.5 % -0.43 [ -0.76, -0.10 ]
Total (95% CI)

1725
1674
100.0 % -0.40 [ -0.52, -0.28 ]
-4
-2
Favours SLIT
Favours Placebo
102
Analysis 1.13. Comparison 1 Sublingual immunotherapy versus placebo, Outcome 13 Total ocular symptom scores: Fixed-effects model.
Comparison: 1 Sublingual immunotherapy versus placebo Outcome: 13 Total ocular symptom scores: Fixed-effects model
Study or subgroup
Sublingual Immunotherapy N Mean(SD) 1.3 (0.3) 12.7 (4.6) 0.7 (0.48) 27.2 (12.6) 5.76 (0.9)
Placebo N 16 10 10 15 19 16 Mean(SD) 2.1 (0.5) 28 (11.1) 1.9 (0.82) 45.3 (16.8) 7 (1.33) 58.29 (41.21)
Weight
Feliziani 1995 Passalacqua 1998 Ariano 2001 Passalacqua 1999 Mortemousque 2003 Palma-Carlos 2006 Panzner 2008 Casanovas 1994 Troise 1995 Khinchi 2004 Cao 2007 Purello-D Ambrosio 1999 Dahl 2006b Voltolini 2001 Wahn 2009 Dubakiene 2003 Sanchez-Palacios 2001 Andre 2003 Vourdas 1998 Didier 2007 Pradalier 1999 de Blay 2007 Valovirta 2006 Horak 1998 Bowen 2004
18 10 10 15 26
0.7 % 0.4 % 0.4 % 0.8 % 1.2 % 0.9 % 0.9 % 0.4 % 0.9 % 1.1 % 1.9 % 0.9 % 16.8 % 0.9 % 7.9 % 3.0 % 1.2 % 2.0 % 1.9 % 8.6 % 3.7 % 3.2 % 2.0 % 1.3 % 1.7 %
-4 -2 0 2 4
-1.92 [ -2.75, -1.09 ] -1.72 [ -2.78, -0.66 ] -1.71 [ -2.77, -0.65 ] -1.19 [ -1.97, -0.40 ] -1.11 [ -1.75, -0.47 ] -1.00 [ -1.73, -0.27 ] -0.91 [ -1.62, -0.20 ] -0.85 [ -1.94, 0.24 ] -0.78 [ -1.51, -0.04 ] -0.66 [ -1.32, 0.01 ] -0.61 [ -1.11, -0.11 ] -0.56 [ -1.30, 0.17 ] -0.56 [ -0.73, -0.40 ] -0.54 [ -1.27, 0.19 ] -0.51 [ -0.76, -0.27 ] -0.50 [ -0.90, -0.10 ] -0.46 [ -1.09, 0.16 ] -0.44 [ -0.92, 0.04 ] -0.38 [ -0.88, 0.11 ] -0.38 [ -0.62, -0.15 ] -0.38 [ -0.73, -0.02 ] -0.33 [ -0.72, 0.05 ] -0.28 [ -0.77, 0.21 ] -0.23 [ -0.85, 0.38 ] -0.22 [ -0.74, 0.31 ]
17 22.85 (27.02) 20 9 15 18 29 14 282 15 131 47 20 26 60.2 (81.25) 1.29 (0.73) 43 (50) 0.87 (0.576) 1.66 (1.03) 158 (174) 0.7 (0.6) 34.6 (39) 0.77 (1.016) 0.24 (0.27) 2 (2) 1.11 (0.91)
15 185.67 (183.85) 6 16 19 37 16 286 15 135 53 20 48 31 148 61 51 33 20 29 2.5 (1.96) 79 (40) 1.32 (0.75) 2.43 (1.39) 268 (202) 1.1 (0.8) 68 (75) 1.34 (1.194) 0.41 (0.39) 3.5 (4) 1.69 (1.48) 0.56 (1.259) 1.4 (1.24) 1.55 (1.53) 11.18 (10.82) 1.1 (0.9) 2.9 (4.12) 2.38 (1.92)
33 0.199 (0.466) 136 62 53 32 21 27 0.95 (1.1) 1.06 (1.02) 7.79 (9.28) 0.8 (1.2) 2 (3.46) 1.96 (1.9)
Favours SLIT
Favours Placebo
(Continued . . . )
103
(. . .
Study or subgroup Sublingual Immunotherapy N La Rosa 1999 Bufe 2008 Dahl 2006a Ott 2008 Durham 2006 Vervloet 2007 Moreno-Ancillo 2007 Hirsch 1997 Rolinck-Werninghaus 2004 Smith 2004 Aydogan 2007 16 117 61 123 141 22 51 15 39 45 9 Mean(SD) 0.23 (0.445) 0.66 (0.76) 0.75 (0.78) 1.28 (1.77) 0.74 (0.78) 1.14 (1.14) 0.48 (0.39) 0.36 (0.69) 6.83 (13.63) 1.09 (1.224) 0.22 (0.43) Placebo N 17 121 32 60 136 21 49 15 38 51 9 Mean(SD) 0.35 (0.629) 0.79 (0.73) 0.88 (0.68) 1.51 (1.93) 0.81 (0.75) 1.24 (1.4) 0.46 (0.31) 0.31 (0.62) 5.15 (9.81) 0.86 (0.748) 0.01 (0.02) Std. Mean Difference IV,Fixed,95% CI 1.0 % 7.3 % 2.6 % 5.0 % 8.5 % 1.3 % 3.1 % 0.9 % 2.4 % 2.9 % 0.5 % Weight
Continued) IV,Fixed,95% CI
Std. Mean Difference
-0.21 [ -0.90, 0.47 ] -0.17 [ -0.43, 0.08 ] -0.17 [ -0.60, 0.26 ] -0.13 [ -0.43, 0.18 ] -0.09 [ -0.33, 0.14 ] -0.08 [ -0.68, 0.52 ] 0.06 [ -0.34, 0.45 ] 0.07 [ -0.64, 0.79 ] 0.14 [ -0.31, 0.59 ] 0.23 [ -0.18, 0.63 ] 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
Favours SLIT
Favours Placebo
APPENDICES 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/1-7 9 exp animals/ 10 exp humans/ 11 9 not (9 and 10) 12 8 not 11 13 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/13-20 22 exp immunotherapy/ 23 immunotherap$.tw. 24 exp desensitization, immunologic/ 25 desensiti$.tw. 26 exp allergens/ 27 allergen$.tw. 28 or/22-27 29 exp administration, sublingual/ 30 sublingual$.tw. 31 SLIT.tw. 32 or/29-31 33 21 and 28 and 32 34 12 and 33 The search lter 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$.tw. 6 or/1-5 7 (animal or animal experiment).sh. 8 human.sh.
9 7 and 8 10 7 not 9 11 6 not 10 12 exp clinical trial/ 13 (clin$ adj3 trial$).tw. 14 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw. 15 exp placebo/ 16 placebo$.tw. 17 random$.tw. 18 exp experimental design/ 19 exp crossover procedure/ 20 exp control group/ 21 exp latin square design/ 22 or/12-21 23 22 not 10 24 23 not 11 25 exp comparative study/ 26 exp evaluation/ 27 exp prospective study/ 28 (control$ or prospectiv$ or volunteer$).tw. 29 or/25-28 30 29 not 10 31 30 not (11 or 23) 32 11 or 24 or 31 33 exp allergic conjunctivitis/ 34 conjunctivitis.tw. 35 exp rhinitis/ 36 exp allergic rhinitis/ 37 rhiniti$.tw. 38 (pollen adj3 allerg$).tw. 39 hayfever.tw. 40 (hay adj2 fever).tw. 41 or/33-40 42 exp immunotherapy/ 43 immunotherap$.tw. 44 exp desensitization/ 45 desensiti$.tw. 46 exp allergen/ 47 allergen$.tw. 48 or/42-47 49 exp sublingual drug administration/ 50 sublingual$.tw. 51 SLIT.tw. 52 41 and 48 and 51 53 32 and 52
106
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* OR prospective 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=(sublingual*) 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=(sublingual*) 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 immunotherapy SLIT 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*
HISTORY
Protocol rst published: Issue 2, 2009 Review rst published: Issue 7, 2011
107
CONTRIBUTIONS OF AUTHORS
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
108
DECLARATIONS OF INTEREST
The Department of Upper Respiratory Medicine, National Heart & Lung Institute, London, UK, headed by Professor Durham, has received nancial support from ALK-Abell, Horsholm, Denmark - manufacturers of allergen extracts. Professor Durham has received lecture fees, ad hoc consultancy payments and research funding from ALK-Abell, 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-Abell. Professor Canonicas department at the University of Genoa, Italy has received research grants from Alk-Abell, Lofarma and Stallergnes - manufacturers of allergen extracts. Professor Sheikh has received honoraria and consultancy fees from ALK-Abell.
SOURCES OF SUPPORT
Internal sources
Imperial College of London and National Heart and Lung Institute, UK. Researchers salary University of Genoa, Italy. Researchers salary
External sources
No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

A summary of ndings table (SoF) was developed and the quality of the evidence was graded using the GRADE approach.
109

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Sublingual immunotherapy for treating allergic conjunctivitis (Review)

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

Sublingual immunotherapy for treating allergic conjunctivitis

Assumed risk Control

Itchy/Gritty eyes Symptom scores

3020 (28 studies)

SMD -0.31 (-0.42 to -0.2)

Watery eyes Symptom scores

2641 (21 studies)

SMD -0.23 (-0.34 to 0.11)

Red eyes Symptom scores

1211 (20 studies)

SMD -0.33 (-0.45 to 0.22)

Eye drops Symptom scores

1038 (13 studies)

SMD -0.1 (-0.22 to 0.03)

SMD -0.21 (-0.55 to 0.13)

SMD 0.35 (0 to 0.69)

Description of the condition

Why it is important to do this review

Description of the intervention

Criteria for considering studies for this review

How the intervention might work

Types of studies We included randomised, double-masked placebo controlled trials of SLIT.

1. Total ocular symptom scores

Data collection and analysis

Search methods for identication of studies

Children and 35.1 adults Adults 34.8

Children and 36 adults Children Children 9.6 10.1

Children Adults Adults

Drops Drops Tablets

Dahl Allergy 2006

Children and 24.9 adults

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

Grass mix Tree pollen

Children and 10-61 adults Adults 36

Phleum pratense Grass mix Mites Betula alba Birch pollen

Feliziani Hirsch Horak Khinchi La Rosa

1995 1997 1998 2004 1999

Adults Children Adults Adults Children

Seasonal Perennial Seasonal Seasonal

Drops Drops Drops Drops Drops

Parietaria ju- Seasonal daica Olea europaea Seasonal

MorenoAncillo Mortemousque Ott

Passalacqua Pfaar Pradalier

2006 2008 1999

Tablets Drops Drops

Children and 29.7 Adults Adults 32

Parietaria ju- Seasonal daica

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

RolinckWerninghaus Rder SanchezPalacios Smith Torres-Lima

Grass mix Cat

Grass mix Phleum pratense

Voltolini Vourdas Wahn Wuthrich

2001 1998 2008 2003

Adults Children Children Children

Drops Drops Tablets Drops

Olea europaea Seasonal Grass mix Grass mix Seasonal Seasonal

Risk of bias in included studies

Tertile analysis based on publication year

I2 1.1 Total ocular 36 symptom scores 3399 59%

SMD, 95% CI -0.38 (-0.44 to -0.31)

-0.41 (-0.53 to -0.28) 59%