title: Allergen immunotherapy for IgE-mediated food allergy: a systematic review and meta-analysis.
abstract: BACKGROUND
  The European Academy of Allergy and Clinical Immunology (EAACI) is developing Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated Food Allergy. To inform the development of clinical recommendations, we sought to critically assess evidence on the effectiveness, safety and cost-effectiveness of AIT in the management of food allergy.
  
  
  METHODS
  We undertook a systematic review and meta-analysis that involved searching nine international electronic databases for randomized controlled trials (RCTs) and nonrandomized studies (NRS). Eligible studies were independently assessed by two reviewers against predefined eligibility criteria. The quality of studies was assessed using the Cochrane Risk of Bias tool for RCTs and the Cochrane ACROBAT-NRS tool for quasi-RCTs. Random-effects meta-analyses were undertaken, with planned subgroup and sensitivity analyses.
  
  
  RESULTS
  We identified 1814 potentially relevant papers from which we selected 31 eligible studies, comprising of 25 RCTs and six NRS, studying a total of 1259 patients. Twenty-five trials evaluated oral immunotherapy (OIT), five studies investigated sublingual immunotherapy, and one study evaluated epicutaneous immunotherapy. The majority of these studies were in children. Twenty-seven studies assessed desensitization, and eight studies investigated sustained unresponsiveness postdiscontinuation of AIT. Meta-analyses demonstrated a substantial benefit in terms of desensitization (risk ratio (RR) = 0.16, 95% CI 0.10, 0.26) and suggested, but did not confirm sustained unresponsiveness (RR = 0.29, 95% CI 0.08, 1.13). Only one study reported on disease-specific quality of life (QoL), which reported no comparative results between OIT and control group. Meta-analyses revealed that the risk of experiencing a systemic adverse reaction was higher in those receiving AIT, with a more marked increase in the risk of local adverse reactions. Sensitivity analysis excluding those studies judged to be at high risk of bias demonstrated the robustness of summary estimates of effectiveness and safety of AIT for food allergy. None of the studies reported data on health economic analyses.
  
  
  CONCLUSIONS
  AIT may be effective in raising the threshold of reactivity to a range of foods in children with IgE-mediated food allergy whilst receiving (i.e. desensitization) and post-discontinuation of AIT. It is, however, associated with a modest increased risk in serious systemic adverse reactions and a substantial increase in minor local adverse reactions. More data are needed in relation to adults, long term effects, the impact on QoL and the cost-effectiveness of AIT.
authors.affiliation: Division of Population Medicine Neuadd Meirionnydd, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: U
authors.initials: U
authors.lastname: Nurmatov
authors.affiliation: Evidence-Based Health Care Ltd, Edinburgh, UK.
authors.forename: S
authors.identifier: http://orcid.org/0000-0002-2823-3258
authors.initials: S
authors.lastname: Dhami
authors.affiliation: Department of Pediatrics, Allergy Unit, University of Messina, Messina, Italy.|Molecular Allergology and Immunomodulation-Department of Pediatric Pneumology and Immunology, Charité Medical University, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Arasi
authors.affiliation: Department of Pediatrics, Allergy Unit, University of Messina, Messina, Italy.
authors.forename: G B
authors.initials: GB
authors.lastname: Pajno
authors.affiliation: Allergy Department, Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors.forename: M
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authors.lastname: Fernandez-Rivas
authors.affiliation: Department of Women and Child Health, Food Allergy Referral Centre Veneto Region, Padua General University Hospital, Padua, Italy.
authors.forename: A
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authors.lastname: Muraro
authors.affiliation: The David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Newport, Isle of WIght, UK.|NIHR Respiratory Biomedial Research Unit and Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: G
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authors.lastname: Roberts
authors.affiliation: Swiss Institute for Allergy and Asthma Research, Davos Platz, Switzerland.
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authors.affiliation: Paediatric Allergy and Clinical Immunology Section, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain.
authors.forename: M
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authors.lastname: Alvaro-Lozano
authors.affiliation: Pediatric Pneumology and Immunology, Charité Universitätsmedizin, Berlin, Germany.|Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Beyer
authors.affiliation: Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark.
authors.forename: C
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authors.lastname: Bindslev-Jensen
authors.affiliation: Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: W
authors.initials: W
authors.lastname: Burks
authors.affiliation: Department of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, MRC & Asthma Centre in Allergic Mechanisms of Asthma, King's College London, St Thomas NHS Foundation Trust, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: du Toit
authors.affiliation: Department of Allergy, Clinical Research Center for Allergy & Rheumatology, Sagamihara National Hospital, Sagamihara, Kanagawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ebisawa
authors.affiliation: University Hospitals of Geneva and Medical School of the University of Geneva, Geneva, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Eigenmann
authors.affiliation: Department of Immunology and Department of Dermatology & Allergology, University Medical Center, Utrecht, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Knol
authors.affiliation: Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Makela
authors.affiliation: Department of Pediatrics, Division of Immunology, Allergy and Rheumatology, Stanford University, Stanford, CA, USA.
authors.forename: K C
authors.identifier: http://orcid.org/0000-0002-2146-2955
authors.initials: KC
authors.lastname: Nadeau
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
authors.forename: L
authors.identifier: http://orcid.org/0000-0003-4705-3583
authors.initials: L
authors.lastname: O'Mahony
authors.affiliation: Department of Allergy, 2nd Pediatric Clinic, University of Athens, Athens, Greece.
authors.forename: N
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Department of Allergy Clinic, Copenhagen University Hospital, Gentofte, Denmark.
authors.forename: L K
authors.initials: LK
authors.lastname: Poulsen
authors.affiliation: Department of Pediatric Allergist, Koç University Hospital, İstanbul, Turkey.
authors.forename: C
authors.initials: C
authors.lastname: Sackesen
authors.affiliation: World Allergy Organization (WAO), Mount Sinai Hospital, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sampson
authors.affiliation: Department of Paediatric Allergy, Division of Asthma, Allergy and Lung Biology, King's College London, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK.
authors.forename: A F
authors.initials: AF
authors.lastname: Santos
authors.affiliation: Department of Otorhinolaryngology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van Ree
authors.affiliation: Nederlands Anafylaxis Netwerk - European Anaphylaxis Taskforce, Dordrecht, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Timmermans
authors.affiliation: Allergy and Respiratory Research Group, Centre of Medical Informatics, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
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mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D003888:Desensitization, Immunologic / Q000379:methods; D005502:Food / Q000009:adverse effects*; D005512:Food Hypersensitivity / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D016017:Odds Ratio; D011788:Quality of Life; D063729:Sublingual Immunotherapy; D016896:Treatment Outcome
chemical_list: D000485:Allergens; D007073:Immunoglobulin E
keywords: allergen immunotherapy; desensitization; food allergy; safety; sustained unresponsiveness