- Study protocol
- Open Access
Allergen immunotherapy for IgE-mediated food allergy: protocol for a systematic review
- Sangeeta Dhami1Email author,
- Ulugbek Nurmatov2,
- Giovanni Battista Pajno3,
- Montserrat Fernandez-Rivas4,
- Antonella Muraro5,
- Graham Roberts6, 7,
- Cezmi Akdis8,
- Montserrat Alvaro-Lozano9,
- Kirsten Beyer10, 11,
- Carsten Bindslev-Jensen12,
- Wesley Burks13,
- George du Toit14,
- Motohiro Ebisawa15,
- Philippe Eigenmann16,
- Edward Knol17, 18,
- Mika Makela19,
- Kari Christine Nadeau20,
- Liam O’Mahony21,
- Nikolaos Papadopoulos22,
- Lars Poulsen23,
- Cansin Sackesen24,
- Hugh Sampson25,
- Alexandra Santos26,
- Ronald van Ree27,
- Frans Timmermans28 and
- Aziz Sheikh29
© Dhami et al 2016
Received: 19 January 2016
Accepted: 17 May 2016
Published: 5 July 2016
The Erratum to this article has been published in Clinical and Translational Allergy 2017 7:31
The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated food allergy. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in IgE-mediated food allergy.
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a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence.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.
The findings from this review will be used to inform the development of recommendations for EAACI’s Guidelines on AIT.
Food allergy is responsible for considerable morbidity and, in some cases, mortality . Epidemiological studies have demonstrated that the prevalence and severity of food allergy may be increasing, particularly in children [2–5]. Food allergies can be divided into IgE-mediated acute allergic reactions manifesting as urticaria, vomiting, wheezing and anaphylaxis, and non-IgE-mediated food allergy which refers to delayed, cell-mediated reactions. This review is focused on IgE-mediated reactions.
Food allergies can be associated with significant reduction in quality of life, both of individuals who suffer from food allergy and their family members . At present, avoidance measures are the cornerstone of management . Difficulties in avoiding responsible food allergens can result in accidental exposure and the risk of triggering potentially life-threatening anaphylaxis . Many individuals with food allergy therefore need to carry adrenaline (epinephrine) auto-injectors in order to self-manage anaphylaxis reactions. This approach is however perceived as restrictive and still leaves patients at risk if accidental exposure occurs.
Alternative approaches are therefore being investigated. In particular, there is considerable international interest in the role of immunotherapy, which involves repeated administration of very small, but gradually increasing doses of the antigens to which individuals are allergic in the hope of allowing safe exposure to the foods in question. Allergen immunotherapy (AIT) has, for example, over the last century become established clinical practice in relation to the treatment of severe pollen, insect venom and drug allergy . However AIT has yet to become established in the routine management of food allergy.
The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for AIT, and this systematic review is one of five inter-linked evidence syntheses that are being 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 food allergy, allergic rhinoconjunctivitis, venom allergy and allergic asthma, and allergy prevention, which will be used to inform the formulation of key clinical recommendations. The focus of this review, which builds on our previous related reviews [10, 11], is on assessing the effectiveness, safety and cost-effectiveness of AIT in the management of IgE-mediated food allergy.
To retrieve randomized controlled trials (RCTs), we will apply the Cochrane highly sensitive search strategy for identifying RCTs in MEDLINE . To retrieve non-randomised studies, i.e. controlled clinical trials (CCT) and quasi-RCTs, we will use the Cochrane Effective Practice and Organisation of Care (EPOC) filter Version 2.4, available on request from the EPOC Group [13, 14]. 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.
Cochrane Library including the:
Health Technology Assessments (HTA)
Economic Evaluations Database (EED)
ISI Web of Science (Thomson Web of Knowledge)
TRIP Database (www.tripdatabase.com)
Clinicaltrials.gov (NIH web).
Current controlled trials (www.controlled-trials.com)
Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au)
We will focus on studies conducted on patients of any age with a physician confirmed diagnosis of IgE-mediated food allergy to milk, eggs, peanuts, tree nuts and other foods in which there is also confirmation of allergic status through positive skin prick tests, specific-IgE or food challenge tests.
Interventions of interest
This review is focused on AIT for different allergens, i.e. milk, eggs, tree nuts, peanuts and other foods, administered through the following routes: oral, sublingual and epicutaneous.
We are interested in studies comparing food allergy AIT with placebo or routine care (i.e. adrenaline autoinjector with or without antihistamines) or no treatment.
RCTs, will be used to investigate effectiveness (i.e. desensitization and tolerance) and impact on disease specific quality of life; health economic analysis will be used to assess cost-effectiveness; 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 individual RCTs. However, given the likelihood that we will find only a limited number of RCTs, we will also search for and include the following non-randomized studies (NRS): controlled before-and-after studies, interrupted-time-series studies and controlled clinical trials. Given the high inherent risk of bias in making inferences from such NRS, we will be very careful in making inferences from these data .
Desensitization (i.e. the ability to safely consume foods containing the allergen in question while on AIT) or tolerance (the ability to consume foods containing the allergen in question after discontinuing AIT) at food challenge, as defined in the relevant studies.
Assessment of changes in disease specific quality of life using a validated instrument; in making this assessment we will focus on the minimal clinically important difference change in quality of life .
Reviews, systematic reviews, discussion papers, non-research letters and editorials
Quantitative studies not employing systematic review or RCT, or employing NRS designs other than those detailed above
Case series (of <300 patients).
All references will be uploaded into the systematic review software Distiller and undergo initial deduplication. Study titles and abstracts will be independently checked by two reviewers according to the above selection criteria and categorized as: included, not included or unsure. Calibration will be undertaken after the first 50 screens to review any discrepancies between reviewers. For those papers in the unsure category, we will retrieve the full-text 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 quality assessment tools. Health economic studies will be assessed using the relevant CASP tool for economic evaluations . RCTs, quasi-RCTs and CCTs 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. The Cochrane Risk of Bias tool will be used for RCTs and the Cochrane ACROBAT tool will be used for NRS . Similarly, we will use the quality assessment form produced by the National Institute for Health and Clinical Excellence (NICE) to critically appraise case series . Any discrepancies will be resolved by discussion or, if agreement cannot be reached, a third reviewer will arbitrate
Data extraction, analysis and synthesis
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 summary data tables will be produced to summarize the literature. If clinically and statistically appropriate, meta-analysis will be undertaken using random-effects modeling given the known clinical heterogeneity between studies. In the event of finding significant statistical heterogeneity between studies (assessed using I2), this will initially be visually inspected and then, if appropriate, be investigated through the pre-specified subgroup and sensitivity analyses (see below). We will preferentially report on RRs with 95 % CIs 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 findings between RCTs and NRS, and by comparing the results from studies that have employed double-blind placebo controlled food challenges versus those using other outcomes to assess for desensitization and/or tolerance.
Children (5–11 years) versus adolescents (12–17 years) versus adults (≥18 years)
Treatment duration: <3 versus ≥3 years
Years of follow up: end of treatment, 2 versus ≥2 years
Route of administration: e.g. SCIT versus SLIT
Allergens used for AIT
Severity of food allergy: mild/moderate versus severe
Primary versus secondary IgE-mediated food allergy.
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.prisma-statement.org/.
This review will involve systematically identifying, critiquing and synthesizing the evidence on the effectiveness, cost-effectiveness and safety of AIT for the management of IgE mediated food allergy. It will build on earlier reviews in this area [10, 11]. 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 report in 2016.
This protocol was drafted by SD and UN and the search strategy was developed by UN. It was revised following critical review by AS and then revised by all co-authors. All authors read and approved the final manuscript.
S. Dhami: support to undertake the systematic review; U. Nurmatov: support to undertake the review; Giovanni Pajno: none; Montserrat Fernandez-Rivas: Participation in immunotherapy clinical trials sponsored by ALK-Abello; A. Muraro: Acting in consulting capacity for ALK, Meda Pharma, Nestle, Nutricia, Novartis. Grants from: Nestlé: Co-investigator for research protocol, Nutricia: Co-investigator for research protocols; G. Roberts: Materials for research programme (ALK-Abello), research grant (ALK-Abello), advisory board (ALK-Abello), speaker (Allergy Therapeutics, ALK-Abelo); C. Akdis: consulting fee Novartis, Boehringer-Ingelheim; stocks Davos Diagnostics, Allimentary Health Pharma Davos; research grant Novartis, Allergopharma; M. Alvaro-Lozano: none; K. Beyer: European Union, German Research Foundation,Berliner Sparkasse, Danone, ThermoFisher Diagnostics, Foundation for the Treatment of Peanut Allergy, author of A European perspective on immunotherapy for food allergies; C. Bindslev-Jensen: Grant from Hal Allergy. Consultancy for Hal Allergy; W Burks: none; G. du Toit: Equity in the FoodMaestro Application. Grants supporting the LEAP Study paid to Kings College, London. Author of the 2015 NEJM LEAP Study manuscripts that do not primarily deal with immunotherapy; M. Ebisawa: none; P. Eigenmann: Grants from LETI, Nestlé, ThermoFisher2, Consulting fee or honorarium from Danone, Novartis, ALK,DBV technologies, Stallergenes, Allergopharma; Edward Knol: Research grant for analysis modified peanut and cows milk allergens from HAL Allergy, Numico research. Consultancy fee from HAL Allergy, advice on peanut allergens; M. Makela: not known; K. Christine Nadeau: none; L. O’Mahony: Consultancy to Alimentary Health Ltd, a probiotic company; N. Papadopoulos: Grant from GSK, NESTLE, MERCK. Consulting fee from GSK, ABBVIE, Novartis, Menarini, Meda, AlK-ABELLO, Allergopharma, Uriach, Stallergenes. Payment for development of educational presentations for Abbvie, Sanofi, Menarini & Meda; L. Poulsen: Grants for Clinical trials in collaboration with ALK, Stallergenes, BioMay, and Anergis; C. Sackesen: Funding from MSD to support laboratory tests for the study ‘Effects of the montelukast therapy on asthma and allergic inflammation in children with food allergy’; H. Sampson: received grants or other research support from NIAID; National Institutes of Health, published an editorial accompanying LEAP study publication; A. Santos: none; R. van Ree: Consultancy for HAL Allergy; F. Timmermans: none with respect to this study; A. Sheikh: support to co-ordinate the undertaking of the systematic review and development of the guidelines.
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- Bock SA, Munoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001–2006. J Allergy Clin Immunol. 2007;119:1016–8.View ArticlePubMedGoogle Scholar
- Sicherer SH, Sampson HA. Peanut allergy: emerging concepts and approaches for an apparent epidemic. J Allergy Clin Immunol. 2007;120:491–503.View ArticlePubMedGoogle Scholar
- Nwaru BI, Hickstein L, Panesar SS, Muraro A, Werfel T, Cardona V, et al. The epidemiology of food allergy in Europe: a systematic review and meta-analysis. Allergy. 2014;69:62–75.View ArticlePubMedGoogle Scholar
- Kotz D, Simpson CR, Sheikh A. Incidence, prevalence, and trends of general practitioner-recorded diagnosis of peanut allergy in England, 2001 to 2005. J Allergy Clin Immunol. 2011;127(623–30):e1.Google Scholar
- Nwaru BI, Hickstein L, Panesar SS, Roberts G, Muraro A, Sheikh A, on behalf of The EAACI Food Allergy & Anaphylaxis Guidelines Group. Prevalence of common food allergies in Europe: a systematic review and meta-analysis. Allergy. 2014;69:992–1007.View ArticlePubMedGoogle Scholar
- DunnGalvin A, Dubois AE, Flokstra-de Blok BM, Hourihane JO. The effects of food allergy on quality of life. Chem Immunol Allergy. 2015;101:235–52.PubMedGoogle Scholar
- Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Beyer K, Bindslev-Jensen C, et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy. 2014;69:1008–25.View ArticlePubMedGoogle Scholar
- Primeau MN, Kagan R, Joseph L, Lim H, Dufreshne C, Duffy C, et al. The psychological burden of peanut allergy as perceived by adults with peanut allergy and the parents of peanut allergic children. Clin Exp Allergy. 2000;30:1135–43.View ArticlePubMedGoogle Scholar
- Calderón MA, Boyle RJ, Penagos M, Sheikh A. Immunotherapy: the meta-analyses. What have we Learned? Immunol Allergy Clin N Am. 2011;31(2):159–73.View ArticleGoogle Scholar
- Nurmatov U, Devereux G, Worth A, Healy L, Sheikh A. Effectiveness and safety of orally administered immunotherapy for food allergies: a systematic review and meta-analysis. Br J Nutr. 2014;111:12–22.View ArticlePubMedGoogle Scholar
- Nurmatov U, Venderbosch I, Devereux G, Simons FE, Sheikh A. Allergen-specific oral immunotherapy for peanut allergy. Cochrane Database Syst Rev. 2012;9:CD009014.Google Scholar
- Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane-handbook.org. Accessed on 3 Sept 2015.
- EPOC Group. http://epoc.cochrane.org/literature-searching-systematic-reviews.
- Cochrane Effective Practice & Organisation of Care (EPOC) Group: Personal communication Michelle Fiander, Information Specialist & Trial Search Co-ordinator. Ottawa, Canada: EPOC; 2012.Google Scholar
- Effective Practice and Organisation of Care Group. What study designs should be included in an EPOC review and what should they be called. http://epoc.cochrane.org/sites/epoc.cochrane.org/files/uploads/EPOC%20Study%20Designs%20About.pdf. Accessed on 9 Dec 2015.
- Salvilla SA, Dubois AE, Flokstra-de Blok BM, Panesar SS, Worth A, Patel S, et al. Disease-specific health-related quality of life instruments for IgE-mediated food allergy. Allergy. 2014;69(7):834–44.View ArticlePubMedGoogle Scholar
- Passalacqua G,Baena-Cagnani C, Bousquet J, Walter Canonica G, Casalet T, Cox L, Durham S, Larenas-Linnemann D, Ledford D, Pawankar R, Potter P, Rosario N, Wallace D, Lockey R. Grading local side effects of sublingual immunotherapy for respiratory allergy: Speaking the same language J Allergy Clin Immunol; 2013. http://www.jacionline.org/article/S0091-6749(13)00528-9/pdf.
- World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. https://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Immunotherapy%20Forms/7b-World-Allergy-Organization-Systemic-Reaction-Grading-systemx.pdf.
- CASP checklist for Economic evaluations. http://media.wix.com/ugd/dded87_3b2bd5743feb4b1aaac6ebdd68771d3f.pdf. Last Accessed on 3 Sept 2015.
- Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions. Version 5.0.2 (Chapter 11, Section 11).Google Scholar
- Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.View ArticlePubMedPubMed CentralGoogle Scholar
- Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.View ArticlePubMedGoogle Scholar