Allergen immunotherapy for insect venom allergy: protocol for a systematic review

Background The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for the Management of Insect Venom Allergy. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in the management of insect venom allergy. Methods We will undertake a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence. Studies will be independently screened against pre-defined eligibility criteria and critically appraised using established instruments. Data will be descriptively and, if possible and appropriate, quantitatively synthesised. Discussion The findings from this review will be used to inform the development of recomendations for EAACI’s Guidelines on AIT.


Background
Hymenoptera venom allergy is a potentially life-threatening allergic reaction following one or more stings to bees, wasps, polistes, hornets or fire ants. The risk of anaphylaxis to hymenoptera stings is greater in adults when compared to children due to increased sting exposure, co-morbidities and concomitant medications in this age group. Systemic reactions have been reported in up to 3 % of adults and 0.34 % of children [1,2].
Symptoms range from large local reactions at the sting site to mild, moderate, and severe systemic reactions. Mild systemic reactions are usually generalized skin symptoms such as flush, urticaria and angioedema. Typically, dizziness, dyspnea, nausea are moderate symptoms while anaphylactic shock, asthma, loss of consciousness, or even cardiac or respiratory arrest all indicate a severe sting reaction. The fear of future reactions usually greatly impairs quality of life. Around a quarter of fatalities from anaphylaxis are triggered by venom allergy [3][4][5].
Patients are advised to carry an emergency kit containing H1-antihistamines, corticosteroids, and adrenaline (epinephrine) depending on their previous sting reaction. The only treatment that can potentially prevent further severe reactions is venom immunotherapy (VIT). This may be effective with long-term clinical benefit and improved quality of life [6,7]. However, despite its lifesaving potential, VIT is still being under-prescribed and under-used in Europe [8].
The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for AIT. This systematic review is one of five inter-linked evidence syntheses that are being

Open Access
Clinical and Translational Allergy *Correspondence: sangeetadhami@hotmail.com 1 Evidence-Based Health Care Ltd, Edinburgh, UK Full list of author information is available at the end of the article undertaken in order to provide a state-of-the-art synopsis of the current evidence base in relation to evaluating AIT for the treatment of insect venom allergy, allergic rhinoconjunctivitis, food allergy and allergic asthma, and allergy prevention. These will be used to inform the formulation of key clinical recommendations for subsequent clinical guidelines. The focus of this review is on assessing the effectiveness, safety and cost-effectiveness of VIT in the treatment of insect venom allergy.

Search strategy
A highly sensitive search strategy has been developed, and validated study design filters will be applied to retrieve all articles pertaining to the use of VIT for insect venom allergy from electronic bibliographic databases. We have conceptualized the search to incorporate the four elements below as shown in Fig. 1.
To retrieve systematic reviews, we will use the systematic review filter developed at McMaster University Health Information Research Unit (HIRU) (http://hiru. mcmaster.ca/hiru/HIRU_Hedges_MEDLINE_Strategies.aspx#Reviews). To retrieve randomized controlled trials (RCTs), we will apply the Cochrane highly sensitive search strategy for identifying RCTs in MEDLINE [9]. To retrieve non-randomized studies, i.e. controlled clinical trials (CCTs), controlled before-and-after (CBA) and interrupted time-series (ITS) studies, we will use the Cochrane Effective Practice and Organisation of Care (EPOC) filter Version 2.4, available on request from the EPOC Group [10,11]. To retrieve case series, we will use the filter developed by librarians at Clinical Evidence: http://clinicalevidence.bmj.com/x/set/static/ebm/ learn/665076.html.
We will search the following databases: • Cochrane Library including: • The search strategy has been developed on OVID MEDLINE and then adapted for the other databases (see "Appendix"). In all cases, the databases will be searched from inception to October 31, 2015. Additional references will be located through searching the references cited by the identified studies, and unpublished work and research in progress will be identified through discussion with experts in the field. We will invite experts who are active in the field from a range of disciplines and regions to add to the list of included studies by identifying additional published and unpublished papers they are aware of and research in progress. There will be no language restrictions employed; where possible, all relevant literature will be translated into English.

Inclusion criteria Patient characteristics
We are interested in identifying studies conducted on patients of any age with a physician confirmed diagnosis of systemic sting reaction to a venom sting from fire ants, bees and bumble bees, and paper wasps and wasps.

Interventions of interest
This review is focused on VIT using different products (purified and non-purified aqueous or depot) and different treatment protocols (conventional, cluster, rush and ultra-rush) adminsitered through the SCIT or SLIT routes.

Comparators
We are interested in studies comparing VIT with placebo or no treatment (i.e. a natural course of the disease).

Study designs
Systematic reviews of RCTs, and RCTs, will be used to investigate effectiveness; health economic analysis will be used to assess cost-effectiveness; and systematic reviews, and RCTs and case series with a minimum of 300 patients will be used to assess safety. We will appraise the evidence by looking at higher levels of evidence such as systematic reviews and/or meta-analyses of RCTs, together with individual RCTs. However, given the likelihood that we will find only a limited number of RCTs, we will also search for and include quasi-RCTs-[i.e. nonrandomized CCTs, controlled before and after (CBA) studies and interrupted time series (ITS) analyses]. Given the high inherent risk of bias in making inferences from quasi-RCTs, clinical recommendations will be based on the findings from randomized controlled trials and the quasi-randomized controlled trials will only be used to guide suggestions on which areas need to be prioritized in future research [12].

Primary
• Efficacy assessed by tolerated sting challenge or field sting both short-term and long-term, where longterm is defined as sustained clinical efficacy after discontinuation of treatment (VIT).

Secondary
• Assessment of disease specific quality of life; • Safety as assessed by local and systemic reactions in accordance with the World Allergy Organization's grading system of side-effects [13,14]; • Health economic analysis from the perspective of the health system/payer.

Exclusion criteria
• Reviews, discussion papers, non-research letters and editorials; • Animal studies; • Quantitative studies not employing systematic review or RCT or quasi-RCT designs; • Qualitative studies; • Case series (<300 patients).

Study selection
All references will be uploaded into the systematic review software Distiller and undergo initial de-duplication. Study titles will be independently checked by two reviewers according to the above selection criteria and categorized as: included, not included or unsure. For those papers in the unsure category, we will retrieve the abstract and re-categorize as above. Any discrepancies will be resolved through discussion and, if necessary, a third reviewer will be consulted. Full text copies of potentially relevant studies will be obtained and their eligibility for inclusion independently assessed. Studies that do not fulfil all of the inclusion criteria will be excluded.

Quality assessment strategy
Quality assessments will independently be carried out on each study by two reviewers using the relevant version of the Critical Appraisal Skills Programme (CASP) quality assessment tool for systematic reviews and health economic evaluations [15]. We will assess the risk of bias of experimental studies using the criteria suggested by the Cochrane EPOC Group [16]. RCTs, CCTs and CBAs will be assessed for generation of allocation sequence, concealment of allocation, baseline outcome measurements, baseline characteristics, incomplete outcome data, blinding of outcome assessor, protection against contamination, selective outcome reporting and other risks of bias using the Cochrane risk of bias tool. For ITS designs, we will also assess the independence of the intervention from secular trends, the pre-specified shape of the intervention and if the intervention may have had an impact on data collection. These methodological assessments will draw on the principles incorporated into the Cochrane EPOC guidelines for assessing intervention studies [17]. Similarly, we will use the quality assessment form produced by the National Institute for Health and Clinical Excellence (NICE) to critically appraise case series [18]. Any discrepancies will be resolved by discussion or, if agreement could not be reached, by arbitration by a third reviewer.

Analysis, data synthesis and reporting
Data will be independently extracted onto a customized data extraction sheet in Distiller by two reviewers, and any discrepancies will be resolved by discussion or, if agreement cannot be reached, by arbitration by a third reviewer.
A descriptive summary with data tables will be produced to summarize the literature. If clinically and statistically appropriate, meta-analysis using either fixed-effect or random-effects modeling will be undertaken [9]. A narrative synthesis of the data will also be undertaken.

Sensitivity and subgroup analyses, and assessment for publication bias
Sensitivity analyses will be undertaken by comparing the summary estimates obtained by excluding studies judged to be at high risk of bias.
Subgroup analyses will be undertaken to compare: • • Comparing outcomes between those with and without co-existent mast cell disease [19].
Where possible, publication bias will be assessed through the creation of funnel plots, and tested by Egger's regression test and Begg's rank correlation test [20,21].

Registration and reporting
This review will be registered with the International Prospective Register of Systematic Reviews (PROSPERO): http://www.crd.york.ac.uk/prospero/. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist will be used to guide the reporting of the systematic review: http://www.prismastatement.org/.

Discussion
This review will involve systematically identifying, critiquing and synthesizing the evidence on the efficacy/ effectiveness, cost-effectiveness and safety of VIT for the management of venom allergy. The findings from this review will be used to inform the development of recommendations for EAACI's Guidelines on AIT. We anticipate that this review will be reported in 2016.