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Food allergen immunotherapy: Current status and prospects for the future

2016; Elsevier BV; Volume: 137; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2016.01.001

1097-6825

Robert A. Wood,

Asthma and respiratory diseases

Food allergy is a common condition for which the only currently approved treatments are avoidance of the allergenic food and administration of emergency medications on accidental exposure. Over the past 10 years, significant advances have been made in the field of food immunotherapy, including oral immunotherapy, sublingual immunotherapy, and, more recently, epicutaneous immunotherapy. Each of these approaches are intended to induce some level of desensitization with chronic or repeated exposure to the allergenic food protein, although the risks and potential benefits of each treatment differ significantly. Although new data are emerging at a rapid pace and progress has been substantial, a number of important issues need to be addressed before introduction of these therapies into clinical practice. Furthermore, it is entirely possible that advances in this field will render these current approaches obsolete over the next 20 to 30 years as new and better therapies are developed. Food allergy is a common condition for which the only currently approved treatments are avoidance of the allergenic food and administration of emergency medications on accidental exposure. Over the past 10 years, significant advances have been made in the field of food immunotherapy, including oral immunotherapy, sublingual immunotherapy, and, more recently, epicutaneous immunotherapy. Each of these approaches are intended to induce some level of desensitization with chronic or repeated exposure to the allergenic food protein, although the risks and potential benefits of each treatment differ significantly. Although new data are emerging at a rapid pace and progress has been substantial, a number of important issues need to be addressed before introduction of these therapies into clinical practice. Furthermore, it is entirely possible that advances in this field will render these current approaches obsolete over the next 20 to 30 years as new and better therapies are developed. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: April 2016. Credit may be obtained for these courses until March 31, 2017.Copyright Statement: Copyright © 2016-2017. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Robert A. Wood, MDDisclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: R. A. Wood has received consultancy fees from Sanofi and Stallergenes; is employed by Johns Hopkins University; has received research support from the National Institutes of Health, DBV Technologies, and Aimmune; has received royalties from UpToDate; and has received payment for developing educational presentations from Medscape.Activity Objectives:1.To review the current status of food immunotherapy, including oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT).2.To discuss the proposed underlying mechanisms involved in food immunotherapy.3.To discuss modified allergen immunotherapy and the potential role for adjunctive therapies currently under consideration.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Malika Gupta, MD, Sayantani B. Sindher, MD, and James Corry, MD.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The exam authors disclosed no relevant financial relationships.Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: April 2016. Credit may be obtained for these courses until March 31, 2017. Copyright Statement: Copyright © 2016-2017. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Robert A. Wood, MD Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: R. A. Wood has received consultancy fees from Sanofi and Stallergenes; is employed by Johns Hopkins University; has received research support from the National Institutes of Health, DBV Technologies, and Aimmune; has received royalties from UpToDate; and has received payment for developing educational presentations from Medscape. Activity Objectives:1.To review the current status of food immunotherapy, including oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT).2.To discuss the proposed underlying mechanisms involved in food immunotherapy.3.To discuss modified allergen immunotherapy and the potential role for adjunctive therapies currently under consideration. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Malika Gupta, MD, Sayantani B. Sindher, MD, and James Corry, MD. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The exam authors disclosed no relevant financial relationships. Food allergy (FA) is very common, affecting up to 8% of young children and 3% to 6% of the entire US population,1Sicherer S.H. Epidemiology of food allergy.J Allergy Clin Immunol. 2011; 127: 594-602Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar, 2Gupta R.S. Springston E.E. Warrier M.R. Smith B. Kumar R. Pongracic J. et al.The prevalence, severity, and distribution of childhood food allergy in the United States.Pediatrics. 2011; 128: e9-e17Crossref PubMed Scopus (1017) Google Scholar, 3Boyce J.A. Assa'a A. Burks A.W. Jones S.M. Sampson H.A. Wood R.A. et al.Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-Sponsored Expert Panel Report.Nutrition. 2011; 27: 253-267Crossref PubMed Scopus (65) Google Scholar, 4Sampson H.A. Aceves S. Bock S.A. James J. Jones S. 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Although many young children with FA will develop natural tolerance over time, for many, it persists into adolescence and adulthood, including most with peanut and tree nut allergy and important subsets of patients with milk and egg allergy.1Sicherer S.H. Epidemiology of food allergy.J Allergy Clin Immunol. 2011; 127: 594-602Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar, 3Boyce J.A. Assa'a A. Burks A.W. Jones S.M. Sampson H.A. Wood R.A. et al.Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-Sponsored Expert Panel Report.Nutrition. 2011; 27: 253-267Crossref PubMed Scopus (65) Google Scholar, 6Skripak J.M. Matsui E.C. Mudd K. Wood R.A. The natural history of IgE-mediated cow's milk allergy.J Allergy Clin Immunol. 2007; 120: 1172-1177Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar, 7Savage J.H. Matsui E.C. Skripak J.M. Wood R.A. The natural history of egg allergy.J Allergy Clin Immunol. 2007; 120: 1413-1417Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar FA causes significant impairment in quality of life8Sicherer S.H. Noone S.A. Munoz-Furlong A. The impact of childhood food allergy on quality of life.Ann Allergy Asthma Immunol. 2001; 87: 461-464Abstract Full Text PDF PubMed Scopus (389) Google Scholar and can lead to nutritional deficiencies9Robbins K.A. Wood R.A. Keet C.A. Milk allergy is associated with decreased growth in US children.J Allergy Clin Immunol. 2014; 134: 1466-1468.e6Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and, even with meticulous avoidance, frequent and potentially life-threatening reactions.10Atkins D. Bock S.A. Fatal anaphylaxis to foods: epidemiology, recognition, and prevention.Curr Allergy Asthma Rep. 2009; 9: 179-185Crossref PubMed Scopus (35) Google Scholar, 11Fleischer D.M. Perry T.T. Atkins D. Wood R.A. Burks A.W. Jones S.M. et al.Allergic reactions to foods in preschool-aged children in a prospective observational food allergy study.Pediatrics. 2012; 130: e25-e32Crossref PubMed Scopus (199) Google Scholar Given the prevalence of FA and its associated morbidities, safe and effective therapies are highly desirable. Immunotherapy relies on the delivery of increasing doses of specific allergens over time with the goal of developing desensitization and eventual tolerance. Although the exact mechanisms underlying allergen immunotherapy are still not fully understood, it is known to induce allergen-specific regulatory T cells, which suppress TH2 responses. This response is coupled with increases in levels of allergen-specific IgG4 antibodies and reductions in mast cell and basophil activation and mediator release.12Akdis M. Akdis C.A. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens.J Allergy Clin Immunol. 2014; 133: 621-631Abstract Full Text Full Text PDF PubMed Scopus (405) Google Scholar, 13Keet C.A. Wood R.A. Emerging therapies for food allergy.J Clin Invest. 2014; 124: 1880-1886Crossref PubMed Scopus (45) Google Scholar, 14Berin M.C. Sicherer S. Food allergy: mechanisms and therapeutics.Curr Opin Immunol. 2011; 23: 794-800Crossref PubMed Scopus (32) Google Scholar, 15Berin M.C. Future therapies for IgE-mediated food allergy.Curr Pediatr Rep. 2014; 2: 119-126Crossref PubMed Scopus (9) Google Scholar Over the past century, immunotherapy has been successfully used to treat asthma, allergic rhinitis, and venom hypersensitivity. Published case reports of immunotherapy for FA date back to at least the 1940s,16Edwards H.E. Oral desensitization in food allergy.Can Med Assoc J. 1940; 43: 234-236PubMed Google Scholar, 17Bauer A. Ekanayake Mudiyanselage S. Wigger-Alberti W. Elsner P. Oral rush desensitization to milk.Allergy. 1999; 54: 894-895Crossref PubMed Scopus (65) Google Scholar, 18Patriarca G. Schiavino D. Nucera E. Schinco G. Milani A. Gasbarrini G.B. Food allergy in children: results of a standardized protocol for oral desensitization.Hepatogastroenterology. 1998; 45: 52-58PubMed Google Scholar, 19Patriarca C. Romano A. Venuti A. Schiavino D. Di Rienzo V. Nucera E. et al.Oral specific hyposensitization in the management of patients allergic to food.Allergol Immunopathol (Madr). 1984; 12: 275-281PubMed Google Scholar, 20Potemkina A.M. Timerbaeva G.M. [Specific desensitization treatment of children with food hypersensitivity by the sublingual method].Pediatriia. 1982; 2: 38-40PubMed Google Scholar but the first randomized placebo-controlled study was not published until 2005.21Enrique E. Pineda F. Malek T. Bartra J. Basagana M. Tella R. et al.Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract.J Allergy Clin Immunol. 2005; 116: 1073-1079Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar In the 1990s, an attempt to use subcutaneous immunotherapy (SCIT) for peanut allergy resulted in an unacceptably high rate of systemic reactions, such that this approach was largely abandoned.22Oppenheimer J.J. Nelson H.S. Bock S.A. Christensen F. Leung D.Y. Treatment of peanut allergy with rush immunotherapy.J Allergy Clin Immunol. 1992; 90: 256-262Abstract Full Text PDF PubMed Scopus (437) Google Scholar Therefore subsequent studies have focused on alternative routes of delivery or potential modification of allergenic proteins in an effort to induce tolerance while at the same time reducing risk. Here we will review the current status of oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT), as well as other novel approaches for the potential treatment of the patient with persistent FA. OIT is accomplished by mixing the allergenic food into a vehicle and ingesting it in gradually increasing doses. Protocols have varied considerably with regard to dosing and the type of food used, with some using commercially available foods (eg, liquid milk) and others using specifically prepared products (eg, defatted peanut flour). Although these therapies can essentially be purchased in the grocery store, most OIT research has been and should be conducted with US Food and Drug Administration (FDA) oversight, which requires Investigational New Drug status with FDA-regulated standards and safeguards. For example, allergenic proteins must be identified and quantified, and the product must be shown to be free of microbial contaminants. Although the details vary considerably, most OIT protocols include an initial dose escalation, followed by a gradual dose build-up and a prolonged maintenance phase (Fig 1).13Keet C.A. Wood R.A. Emerging therapies for food allergy.J Clin Invest. 2014; 124: 1880-1886Crossref PubMed Scopus (45) Google Scholar, 23Hofmann A.M. Scurlock A.M. Jones S.M. Palmer K.P. Lokhnygina Y. Steele P.H. et al.Safety of a peanut oral immunotherapy protocol in children with peanut allergy.J Allergy Clin Immunol. 2009; 124 (e1-6): 286-291Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 24Jones S.M. Burks A.W. Dupont C. State of the art on food allergen immunotherapy: oral, sublingual, and epicutaneous.J Allergy Clin Immunol. 2014; 133: 318-323Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar Initial dose escalation is typically conducted on a single day, beginning with an extremely small dose that is rapidly increased (eg, starting with 0.1 mg of the food protein and increasing in doubling doses to a maximum of 10 to 25 mg).25Keet C.A. Frischmeyer-Guerrerio P.A. Thyagarajan A. Schroeder J.T. Hamilton R.G. Boden S. et al.The safety and efficacy of sublingual and oral immunotherapy for milk allergy.J Allergy Clin Immunol. 2012; 129 (e1-5): 448-455Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar, 26Burks A.W. Jones S.M. Wood R.A. Fleischer D.M. Sicherer S.H. Lindblad R.W. et al.Oral immunotherapy for treatment of egg allergy in children.N Engl J Med. 2012; 367: 233-243Crossref PubMed Scopus (534) Google Scholar, 27Varshney P. Jones S.M. Scurlock A.M. Perry T.T. Kemper A. Steele P. et al.A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.J Allergy Clin Immunol. 2011; 127: 654-660Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar The intent of the initial escalation is to begin and remain at subthreshold levels and identify a safe starting dose for home administration. In the build-up phase dose escalations, which vary in increments from 25% to 100% in different protocols, are typically conducted under a physician's supervision every 1 to 2 weeks, with daily home doses in between until the target maintenance dose is achieved. Studies also differ markedly in both the maintenance dose and duration of treatment, with doses ranging from 300 to 4000 mg and durations ranging from months to years. Table I, Table II, Table III25Keet C.A. Frischmeyer-Guerrerio P.A. Thyagarajan A. Schroeder J.T. Hamilton R.G. Boden S. et al.The safety and efficacy of sublingual and oral immunotherapy for milk allergy.J Allergy Clin Immunol. 2012; 129 (e1-5): 448-455Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar, 26Burks A.W. Jones S.M. Wood R.A. Fleischer D.M. Sicherer S.H. Lindblad R.W. et al.Oral immunotherapy for treatment of egg allergy in children.N Engl J Med. 2012; 367: 233-243Crossref PubMed Scopus (534) Google Scholar, 27Varshney P. Jones S.M. Scurlock A.M. Perry T.T. Kemper A. Steele P. et al.A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.J Allergy Clin Immunol. 2011; 127: 654-660Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar, 28Vickery B.P. Scurlock A.M. Kulis M. Steele P.H. Kamilaris J. Berglund J.P. et al.Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy.J Allergy Clin Immunol. 2014; 133: 468-475Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar, 29Jones S.M. Pons L. Roberts J.L. Scurlock A.M. Perry T.T. Kulis M. et al.Clinical efficacy and immune regulation with peanut oral immunotherapy.J Allergy Clin Immunol. 2009; 124 (e1-97): 292-300Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar, 30Blumchen K. Ulbricht H. Staden U. Dobberstein K. Beschorner J. de Oliveira L.C. et al.Oral peanut immunotherapy in children with peanut anaphylaxis.J Allergy Clin Immunol. 2010; 126: 83-91.e1Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar, 31Narisety S.D. Frischmeyer-Guerrerio P.A. Keet C.A. Gorelik M. Schroeder J. Hamilton R.G. et al.A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy.J Allergy Clin Immunol. 2015; 135: 1275-1282Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 32Anagnostou K. Clark A. King Y. Islam S. Deighton J. Ewan P. Efficacy and safety of high-dose peanut oral immunotherapy with factors predicting outcome.Clin Exp Allergy. 2011; 41: 1273-1281Crossref PubMed Scopus (137) Google Scholar, 33Anagnostou K. Islam S. King Y. Islam S. Deighton J. Ewan P. Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial.Lancet. 2014; 383: 1297-1304Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar, 34Buchanan A.D. Green T.D. Jones S.M. Scurlock A.M. Christie L. Althage K.A. et al.Egg oral immunotherapy in nonanaphylactic children with egg allergy.J Allergy Clin Immunol. 2007; 119: 199-205Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar, 35Vickery B.P. Pons L. Kulis M. Steele P. Jones S.M. Burks A.W. Individualized IgE-based dosing of egg oral immunotherapy and the development of tolerance.Ann Allergy Asthma Immunol. 2010; 105: 444-450Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 36Meglio P. Bartone E. Plantamura M. Arabito E. Giampietro P.G. A protocol for oral desensitization in children with IgE-mediated cow's milk allergy.Allergy. 2004; 59: 980-987Crossref PubMed Scopus (315) Google Scholar, 37Longo G. Barbi E. Berti I. Meneghetti R. Pittalis A. Ronfani L. et al.Specific oral tolerance induction in children with very severe cow's milk-induced reactions.J Allergy Clin Immunol. 2008; 121: 343-347Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 38Skripak J.M. Nash S.D. Rowley H. Brereton N.H. Oh S. Hamilton R.G. et al.A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy.J Allergy Clin Immunol. 2008; 122: 1154-1160Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar, 39Martorell A. De la Hoz B. Ibanez M.D. Bone J. Terrados M.S. Michavila A. et al.Oral desensitization as a useful treatment in 2-year-old children with cow's milk allergy.Clin Exp Allergy. 2011; 41: 1297-1304Crossref PubMed Scopus (149) Google Scholar, 40Pajno G.B. Caminiti L. Ruggeri P. De Luca R. Vita D. La Rosa M. et al.Oral immunotherapy for cow's milk allergy with a weekly up-dosing regimen: a randomized single-blind controlled study.Ann Allergy Asthma Immunol. 2010; 105: 376-381Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 41Wood R.A. Kim J.S. Lindblad R. Nadeau K. Henning A.K. Dawson P. et al.A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy.J Allergy Clin Immunol. 2016; 137: 1103-1110Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar show some of the variability in study design in terms of maintenance dosing, duration of therapy, and outcomes.Table IPeanut OIT studiesReferenceYearDesignSamples sizeSubject age (y)Maintenance dose (mg)DurationPrimary outcomeJones et al29Jones S.M. Pons L. Roberts J.L. Scurlock A.M. Perry T.T. Kulis M. et al.Clinical efficacy and immune regulation with peanut oral immunotherapy.J Allergy Clin Immunol. 2009; 124 (e1-97): 292-300Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar2009Open label291-16180036 mo93% Passed 3.9-g peanut OFCBlumchen et al30Blumchen K. Ulbricht H. Staden U. Dobberstein K. Beschorner J. de Oliveira L.C. et al.Oral peanut immunotherapy in children with peanut anaphylaxis.J Allergy Clin Immunol. 2010; 126: 83-91.e1Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar2010Randomized open label233-145007-d Rush escalation, 8-wk maintenance period64% Reached maintenance of 500 mg of peanutVarshney et al27Varshney P. Jones S.M. Scurlock A.M. Perry T.T. Kemper A. Steele P. et al.A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.J Allergy Clin Immunol. 2011; 127: 654-660Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar2011Randomized, placebo controlled193-11200048 wk84% Passed 5000-mg peanut OFCAnagnostou et al32Anagnostou K. Clark A. King Y. Islam S. Deighton J. Ewan P. Efficacy and safety of high-dose peanut oral immunotherapy with factors predicting outcome.Clin Exp Allergy. 2011; 41: 1273-1281Crossref PubMed Scopus (137) Google Scholar2011Open label224-1880032 wk64% Tolerated 6.6-g OFCAnagnostou et al33Anagnostou K. Islam S. King Y. Islam S. Deighton J. Ewan P. Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial.Lancet. 2014; 383: 1297-1304Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar2014Randomized, controlled397-1680026 wk62% Tolerated 1400-mg challengeVickery et al28Vickery B.P. Scurlock A.M. Kulis M. Steele P.H. Kamilaris J. Berglund J.P. et al.Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy.J Allergy Clin Immunol. 2014; 133: 468-475Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar2014Open label241-16Up to 4000Up to 5 y50% SU to 5000-mg OFC after 4-wk avoidanceNarisety et al31Narisety S.D. Frischmeyer-Guerrerio P.A. Keet C.A. Gorelik M. Schroeder J. Hamilton R.G. et al.A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy.J Allergy Clin Immunol. 2015; 135: 1275-1282Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar2014Randomized, placebo controlled167-13200012 moOIT > SLIT in OFC threshold, low rate of SU Open table in a new tab Table IIEgg OIT studiesReferenceYearDesignSample sizeSubject age (y)Maintenance dose (g)Duration (mo)Primary outcomeBuchanan et al34Buchanan A.D. Green T.D. Jones S.M. Scurlock A.M. Christie L. Althage K.A. et al.Egg oral immunotherapy in nonanaphylactic children with egg allergy.J Allergy Clin Immunol. 2007; 119: 199-205Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar2007Open label71-160.32457% Passed 8-g OFCVickery et al35Vickery B.P. Pons L. Kulis M. Steele P. Jones S.M. Burks A.W. Individualized IgE-based dosing of egg oral immunotherapy and the development of tolerance.Ann Allergy Asthma Immunol. 2010; 105: 444-450Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar2010Open label83-130.3-3.618-5075% Passed OFC 1 mo after stopping OITBurks et al26Burks A.W. Jones S.M. Wood R.A. Fleischer D.M. Sicherer S.H. Lindblad R.W. et al.Oral immunotherapy for treatment of egg allergy in children.N Engl J Med. 2012; 367: 233-243Crossref PubMed Scopus (534) Google Scholar2012Randomized, placebo controlled405-111.62275% Passed 10-g OFC but SU in only 28% at 6-8 wk later Open table in a new tab Table IIIMilk OIT studiesReferenceYearDesignSamples sizeSubject age (y)Maintenance doseDurationPrimary outcomeMeglio et al36Meglio P. Bartone E. Plantamura M. Arabito E. Giampietro P.G. A protocol for oral desensitization in children with IgE-mediated cow's milk allergy.Allergy. 2004; 59: 980-987Crossref PubMed Scopus (315) Google Scholar2004Open label216-10200 mL6 mo72% Desensitization to 200 mL of cow's milk dailyLongo et al37Longo G. Barbi E. Berti I. Meneghetti R. Pittalis A. Ronfani L. et al.Specific oral tolerance induction in children with very severe cow's milk-induced reactions.J Allergy Clin Immunol. 2008; 121: 343-347Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar2008Randomized, open label305-17150 mL10-d Rush escalation, 1 y of maintenance36% Tolerant (≥150 mL) and 54% partially tolerant (5-150 mL)Skripak et al38Skripak J.M. Nash S.D. Rowley H. Brereton N.H. Oh S. Hamilton R.G. et al.A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy.J Allergy Clin Immunol. 2008; 122: 1154-1160Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar2008Randomized, placebo controlled136-17500 mg23 wkMedian OFC threshold increased from 40 to 5,140 mg after OITNarisety et al31Narisety S.D. Frischmeyer-Guerrerio P.A. Keet C.A. Gorelik M. Schroeder J. Hamilton R.G. et al.A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy.J Allergy Clin Immunol. 2015; 135: 1275-1282Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar2009Open label (follow-up)136-16500-4,000 mg3-17 moMedian OFC threshold of 7,000 mg (with 33% tolerating 16,000 mg)Pajno et al40Pajno G.B. Caminiti L. Ruggeri P. De Luca R. Vita D. La Rosa M. et al.Oral immunotherapy for cow's milk allergy with a weekly up-dosing regimen: a randomized single-blind controlled study.Ann Allergy Asthma Immunol. 2010; 105: 376-381Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar2010Randomized, placebo controlled154-10200 mL18 wk67% Tolerant to 200 mL of cow's milkMartorell et al39Martorell A. De la Hoz B. Ibanez M.D. Bone J. Terrados M.S. Michavila A. et al.Oral desensitization as a useful treatment in 2-year-old children with cow's milk allergy.Clin Exp Allergy. 2011; 41: 1297-1304Crossref PubMed Scopus (149) Google Scholar2011Randomized, placebo controlled302-3200 mL1 y90% Showing complete desensitizationKeet et al25Keet C.A. Frischmeyer-Guerrerio P.A. Thyagarajan A. Schroeder J.T. Hamilton R.G. Boden S. et al.The safety and efficacy of sublingual and oral immunotherapy for milk allergy.J Allergy Clin Immunol. 2012; 129 (e1-5): 448-455Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar2012Randomized, placebo controlled20 for OIT6-171,000-2,000 mg60 wk70% Desensitized to 8-g OFC, SU in 40% after 6 wkWood et al41Wood R.A. Kim J.S. Lindblad R. Nadeau K. Henning A.K. Dawson P. et al.A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy.J Allergy Clin Immunol. 2016; 137: 1103-1110Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar2015Omalizumab DBPC, open-label OIT577-323,300 mg24 mo80% Desensitized to