PracticeparameterFoodallergy:Apracticeparameterupdate—2014HughA.S - PDF document

PracticeparameterFoodallergy:Apracticeparameterupdate—2014HughA.Sampson,MD,SeemaAceves,MD,PhD,S.AllanBock,MD,JohnJames,MD,StacieJones,MD,DavidLang,MD,KariNadeau,MD,PhD,AnnaNowak-Wegrzyn,MD,JohnOppenheimer,MD,TamaraT.Perry,MD,ChristopherRandolph,MD,ScottH.Sicherer,MD,RonaldA.Simon,MD,BrianP.Vickery,MD,andRobertWood,MDChiefEditors:HughA.Sampson,MD,andChristopherRandolph,MDMembersoftheJointTaskForceonPracticeParameters:DavidBernstein,MD,JoannBlessing-Moore,MD,DavidKhan,MD,DavidLang,MD,RichardNicklas,MD,JohnOppenheimer,MD,JayPortnoy,MD, Keywords:Foodallergy,foodallergen,cross-reactivity,adversefoodreactions,IgE-mediatedfoodallergy,eosinophilicPreviouslypublishedpracticeparametersoftheJointTaskForceonPracticeParametersforAllergyandImmunologyareavailableathttp://www.JCAAI.orghttp://www.allergyparameters.orgCONTRIBUTORSTheJointTaskForcehasmadeaconcertedefforttoacknowl-edgeallcontributorstothisparameter.Ifanycontributorshavebeenexcludedinadvertently,theTaskForcewillensurethatappropriaterecognitionofsuchcontributionsismadesub-sequently.WORKGROUPCHAIRHughA.Sampson,MDJaffeFoodAllergyInstituteDepartmentofPediatricsIcahnSchoolofMedicineatMountSinaiNewYork,NewYorkJOINTTASKFORCELIAISONChristopherRandolphDepartmentofPediatrics/Allergy/ImmunologyYaleAfÞliatedHospitalsCenterforAllergy,Asthma,&ImmunologyWaterbury,ConnecticutJOINTTASKFORCEMEMBERSDavidI.Bernstein,MDDepartmentsofClinicalMedicineandEnvironmentalDivisionofAllergy/ImmunologyUniversityofCincinnatiCollegeofMedicineCincinnati,OhioJoannBlessing-Moore,MDDepartmentsofMedicineandPediatricsStanfordUniversityMedicalCenterDepartmentofImmunologyPaloAlto,CaliforniaDavidA.Khan,MDDepartmentofInternalMedicineUniversityofTexasSouthwesternMedicalCenterDallas,TexasDavidM.Lang,MDAllergy/ImmunologySectionRespiratoryInstituteAllergyandImmunologyFellowshipTrainingProgramClevelandClinicFoundationCleveland,OhioRichardA.Nicklas,MDDepartmentofMedicineGeorgeWashingtonMedicalCenterWashington,DCJohnOppenheimer,MDDepartmentofInternalMedicineNewJerseyMedicalSchoolPulmonaryandAllergyAssociatesMorristown,NewJerseyJayM.Portnoy,MDSectionofAllergy,Asthma&ImmunologyChildrenÕsMercyHospitalDepartmentofPediatricsUniversityofMissouriÐKansasCitySchoolofMedicineKansasCity,MissouriDianeE.Schuller,MDDepartmentofPediatricsPennsylvaniaStateUniversityMiltonS.HersheyMedicalHershey,PennsylvaniaSheldonL.Spector,MDDepartmentofMedicineUCLASchoolofMedicineLosAngeles,CaliforniaStephenA.Tilles,MDDepartmentofMedicineUniversityofWashingtonSchoolofMedicineRedmond,WashingtonDanaWallace,MDDepartmentofMedicineNovaSoutheasternUniversityCollegeofOsteopathicDavie,FloridaPARAMETERWORKGROUPMEMBERSSeemaAceves,MD,PhDEosinophilicGastrointestinalDisordersClinicDivisionofAllergy,ImmunologyDepartmentsofPediatricsandMedicineUniversityofCalifornia,SanDiegoRadyChildrenÕsHospitalSanDiego,CaliforniaJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL S.AllanBock,MDDepartmentofPediatricsNationalJewishHealthDenver,ColoradoDepartmentofPediatricsUniversityofColoradoSchoolofMedicineAurora,ColoradoJohnM.James,MDPrivateClinicalPracticeColoradoAllergyandAsthmaCenters,PCFortCollins,ColoradoStacieJones,MDDepartmentofPediatricsAllergyandImmunologyUniversityofArkansasforMedicalSciencesArkansasChildrenÕsHospitalLittleRock,ArkansasDavidM.Lang,MDAllergy/ImmunologySectionDivisionofMedicineAllergyandImmunologyFellowshipTrainingProgramClevelandClinicFoundationCleveland,OhioKariNadeau,MD,PhDDepartmentofAllergy,AsthmaandImmunologyStanfordUniversitySchoolofMedicineStanford,CaliforniaAnnaNowak-Wegrzyn,MDDepartmentofPediatricsJaffeFoodAllergyInstituteDivisionofAllergyandImmunologyIcahnSchoolofMedicineatMountSinaiNewYork,NewYorkJohnOppenheimer,MDDepartmentofInternalMedicineNewJerseyMedicalSchoolPulmonaryandAllergyAssociatesMorristown,NewJerseyTamaraT.Perry,MDDepartmentofPediatricsAllergyandImmunologyDivisionUniversityofArkansasforMedicalSciencesArkansasChildrenÕsHospitalLittleRock,ArkansasScottH.Sicherer,MDDepartmentofPediatricsPediatricAllergyandImmunologyIcahnSchoolofMedicineatMountSinaiJaffeFoodAllergyInstituteNewYork,NewYorkRonaldA.Simon,MDDivisionofAllergy,Asthma&ImmunologyScrippsClinicDepartmentofExperimental&MolecularMedicineScrippsResearchInstituteLaJolla,CaliforniaBrianP.Vickery,MDDepartmentofPediatricsUniversityofNorthCarolinaSchoolofMedicineChapelHill,NorthCarolinaRobertWood,MDDepartmentofPediatricsandInternationalHealthDivisionofPediatricAllergyandImmunologyJohnsHopkinsUniversitySchoolofMedicineBaltimore,MarylandTABLEOFCONTENTSI.ClassiÞcationofmajorfoodallergens,cross-reactivities,geneticallymodiÞedfoods,andclinicalimplicationsA.ClassiÞcationB.Cross-reactivityC.GeneticallymodiÞedorganismsinfoodsandthepotentialforallergenicityII.MucosalimmuneresponsesinducedbyfoodsIII.TheclinicalspectrumoffoodallergyA.CategoriesofadversefoodreactionsB.DeÞnitionsofspeciÞcfood-inducedallergicconditionsIV.Prevalence,naturalhistory,andpreventionA.NaturalhistoryB.PreventionoffoodallergyV.AdversereactionstofoodadditivesVI.Diagnosisoffoodallergy,differentialdiagnosis,anddiagnosticalgorithmA.DiagnosisofIgE-mediatedfoodallergyB.Non-IgEmediated:FPIES,allergicproctocolitis,andC.EosinophilicesophagitisD.EosinophilicgastroenteritisVII.Managementoffoodallergyandfood-dependent,exercise-inducedanaphylaxisVIII.EmergingtherapiesforfoodallergyIX.ManagementinspecialsettingsJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL CLASSIFICATIONOFRECOMMENDATIONSANDEVIDENCERecommendationratingscaleCategoryofevidenceIaEvidencefrommeta-analysisofrandomizedcontrolledIbEvidencefromatleast1randomizedcontrolledtrialIIaEvidencefromatleast1controlledstudywithoutIIbEvidencefromatleast1othertypeofquasiexperimentalstudyIIIEvidencefromnonexperimentaldescriptivestudies,suchascomparativestudiesIVEvidencefromexpertcommitteereportsoropinionsorclinicalexperienceofrespectedauthoritiesorbothStrengthofrecommendation*ADirectlybasedoncategoryIevidenceBDirectlybasedoncategoryIIevidenceorextrapolatedrecommendationfromcategoryIevidenceCDirectlybasedoncategoryIIIevidenceorextrapolatedrecommendationfromcategoryIorIIevidenceDDirectlybasedoncategoryIVevidenceorextrapolatedrecommendationfromcategoryI,II,orIIIevidenceLBLaboratorybasedNRNotratedSUMMARYOFCONFLICTOFINTERESTDISCLOSURESThefollowingisasummaryofinterestsdisclosedonworkgroupmembersÕconßictofinterestdisclosurestatements(notincludinginformationconcerningfamilymemberinterests).Completedconßictofinterestdisclosurestatementsareavailableonrequest. StatementStrongrecommendation(StrRec)AstrongrecommendationmeansthebeneÞtsoftherecommendedapproachclearlyexceedtheharms(orthattheharmsclearlyexceedthebeneÞtsinthecaseofastrongnegativerecommendation)andthatthequalityofthesupportingevidenceisexcellent(gradeAorB).*InsomeclearlyidentiÞedcircumstances,strongrecommendationsmightbemadebasedonlesserevidencewhenhigh-qualityevidenceisimpossibletoobtainandtheanticipatedbeneÞtsstronglyoutweightheCliniciansshouldfollowastrongrecommendationunlessaclearandcompellingrationaleforanalternativeapproachispresent.Moderate(Mod)ArecommendationmeansthebeneÞtsexceedtheharms(orthattheharmsexceedthebeneÞtsinthecaseofanegativerecommendation),butthequalityofevidenceisnotasstrong(gradeBorC).*InsomeclearlyidentiÞedcircumstances,recommendationsmightbemadebasedonlesserevidencewhenhigh-qualityevidenceisimpossibletoobtainandtheanticipatedbeneÞtsoutweightheharms.Cliniciansshouldalsogenerallyfollowarecommendationbutshouldremainalerttonewinformationandsensitivetopatientpreferences.Weak(Weak)Anoptionmeansthateitherthequalityofevidencethatexistsissuspect(gradeD)*orthatwell-donestudies(gradeA,B,orC)*showlittleclearadvantagetooneapproachversusanother.Cliniciansshouldbeßexibleintheirdecisionmakingregardingappropriatepractice,althoughtheymightsetboundsonalternatives;patientpreferenceshouldhaveasubstantialinßuencingrole.Norecommendation(NoRec)Norecommendationmeansthereisbothalackofpertinentevidence(gradeD)*andanunclearbalancebetweenbeneÞtsandharms.CliniciansshouldfeellittleconstraintintheirdecisionmakingandbealerttonewpublishedevidencethatclariÞesthebalanceofbeneÞtversusharm;patientpreferenceshouldhaveasubstantialinßuencingrole. WorkgroupmemberDisclosuresHughA.Sampson,MDAllerteinTherapeuticsÐConsultantFoodAllergyResearchandEducation(FARE)ÐMedicalAdvisoryBoard,unpaidNovartisÐConsultant,unpaidDBVScientiÞcAdvisoryBoard,unpaidThermoFisherScientiÞcÐEAACItravelexpensesandhonorariumUCBÐXXNationalCongressoftheMexicanPediatricSpecialistsinClinicalImmunologyandAllergyÐTravelexpensesandhonorariumNationalInstituteofAllergyandInfectiousDiseases(NIAID)ÐResearchgrantFAREÐResearchgrantUniversityofNebraska(FARRP)ÐConsultantAllergyandAsthmaFoundationofAmericaÐConsultantJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL WorkgroupmemberDisclosuresSeemaAceves,MD,PhDMeritagePharmaÐPatentroyaltiesS.AllanBock,MDFoodAllergyandAnaphylaxisNetworkÑMedicalAdvisoryBoardNationalJewishHealthÐResearchafÞliateJohnJames,MDAmericanBoardofAllergyandImmunologyÐMedicalAdvisoryBoardParentsofAsthmaticandAllergicChildrenÐMedicalAdvisoryBoardStacieJones,MDNationalInstitutesofHealth(NIH)/NIAIDÐResearchgrantNationalPeanutBoardÐResearchgrantFAREÐAdvisoryboard;researchgrantSanoÞ-AventisÐSteeringCommitteeMemberNIAIDSafetyMonitoringCommitteeÐGrantreviewNIAIDStudySectionÐAdHocReviewAAAAIÐSpeakerIndianaUniversityMedicalSchoolandRileyChildrenÕsHospitalÐSpeakerSpanishSocietyofAllergy&ClinicalImmunology(SEAIC),Madrid,SpainÐSpeakerOregonAllergy,Asthma&ImmunologySocietyÐSpeakerDavidLang,MDTeraÐSpeakerSanoÞ-AventisÐAdvisoryBoardMerckÐAdvisoryBoard;speakerAstra-ZenecaÐSpeakerGenentechÐSpeakerGlaxoSmithKlineÐSpeakerGenentech/NovartisÐResearchgrantKariNadeau,MD,PhDNIAIDÐResearchgrantFAREÐResearchgrantAnnaNowak-Wegrzyn,MDMerckÐAdvisoryBoardFAREÐGrantNestleÐGrantNewYorkAllergyandAsthmaSocietyÐExecutiveCommitteeMemberJohnOppenheimer,MDTamaraT.Perry,MDNIH/NHLBIÐResearchgrantNIH/NIAIDÐResearchgrantNIHNationalCenterforMinorityHealthDisparitiesÐResearchgrantARCenterforClinicalandTranslationResearchÐResearchgrantChristopherRandolph,MDGlaxoSmithKlineÐConsultant;speaker;honorarium;researchgrantAstraÐConsultant;AdvisoryBoard;speaker;honorarium;researchgrantMerck-Consultant;speaker;honorarium;researchgrantGenentech/Novartis-Consultant;speaker;honorarium;researchgrantBaxterÐSpeakerDyaxÐResearchgrantDeyÐSpeakerAlcon-Speaker;honorarium;researchgrantISTA(Bepreve)ÐSpeaker;honorariumSunovion(Sepracor)ÐSpeakerCSFBehringÐSpeakerPharmaxisÐProvidedadvertisementTEVAÐSpeaker;researchgrantConnecticutAllergySocietyÐOfÞcerScottH.Sicherer,MDAmericanAcademyofPediatricsÐOfÞcerAmericanBoardofAllergyImmunologyÐBoardMemberAAAAIÐSpeakerJournalofAllergyandClinicalImmunologyJACI-InPracticeÐAssociateEditorNIH/NIAIDÐGrantsFAREÐConsultantFoodAllergyResearchandEducationÐMedicaladvisor/consultantNovartis-ConsultantRonaldA.Simon,MDNovartisÐSpeakersÕbureauNovartisÐResearchsupportMerckÐSpeakersÕbureauGlaxoSmithKlineÐSpeakersÕbureau(Continued)JALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL ResolutionofnondisqualifyinginterestsTheJointTaskForcerecognizesthatexpertsinaÞeldarelikelytohaveintereststhatcouldcomeintoconßictwithdevelopmentofacompletelyunbiasedandobjectivepracticeparameter.AprocesshasbeendevelopedtopreventpotentialconßictsfrominßuencingtheÞnaldocumentinanegativewaytotakeadvantageofthatexpertise.Attheworkgrouplevel,memberswhohaveapotentialconßictofinteresteitherdonotparticipateindiscussionsconcerningtopicsrelatedtothepotentialconßict,oriftheydowriteasectiononthattopic,theworkgroupcompletelyrewritesitwithouttheirinvolve-menttoremovepotentialbias.Inaddition,theentiredocumentisreviewedbytheJointTaskForce,andanyapparentbiasisremovedatthatlevel.Finally,thepracticeparameterissentforreviewbothbyinvitedreviewersandbyanyonewithaninterestinthetopicbypostingthedocumentontheWebsitesoftheACAAIandAAAAI.ThepracticeparameteronfoodallergywaslastupdatedinandfocusedprimarilyonIgE-mediatedfoodallergy.Intheensuingyears,therehavebeenconsiderableadvancesintheÞeldinmanyareas,includingourbasicunderstandingoffoodaller-gens,diagnostictesting,nonÐIgE-mediateddisorders,andman-agementofvariousfood-inducedallergicreactions.In2010,theNIAIDÔÔGuidelinesonthediagnosisandmanagementoffoodal-lergyÕÕwerepublished,providingacomprehensivereviewofthescientiÞcliteratureandexpertopiniononfoodallergy.GiventhemanyadvancesintheÞeld,theJointTaskForceonPracticePa-rametersappointedaworkinggrouptoreviewandupdatethestandingpracticeparameters.TheworkinggroupreliedheavilyontheNIAIDGuidelinesandfocusedonadvancessincethepub-licationofthatlandmarkdocument.THEJOINTTASKFORCEONPRACTICEPARAMETERSTheJointTaskForceonPracticeParameters(JTF)isa13-membertaskforceconsistingof6representativesassignedbytheAAAAI,6bytheACAAI,and1bytheJointCouncilofAllergyandImmunology.Thistaskforceoverseesthedevelopmentofpracticeparameters,selectstheworkgroupchairorchairs,andreviewsdraftsoftheparametersforaccuracy,practicality,clarity,andbroadutilityoftherecommendationsforclinicalpractice.FOODALLERGY:APRACTICEPARAMETERUPDATEÑ2014WORKGROUPTheFoodAllergy:APracticeParameterUpdate2014Work-groupwascommissionedbytheJTFtodevelopapracticeparameterthataddressesrecentadvancesintheÞeldoffoodallergyandtheoptimalmethodsofdiagnosisandmanagementbasedonanassessmentofthemostcurrentliterature.TheChair(HughA.Sampson,MD)invitedworkgroupmemberstoparticipateintheparameterdevelopmentwhoareconsideredtobeexpertsintheÞeldoffoodallergy.WorkgroupmembershavebeenvettedforÞnancialconßictofinterestbytheJTF,andtheirconßictsofinteresthavebeenlistedinthisdocumentandarepostedontheJTFWebsiteathttp://www.allergyparameters.orgThechargetotheworkgroupwastouseasystematicliteraturereviewinconjunctionwithconsensusexpertopinionandworkgroup-identiÞedsupplementarydocumentstodevelopapracticeparameterthatevaluatesthecurrentstateofthescienceregardingfoodallergy.PROTOCOLFORFINDINGEVIDENCETheNIAIDguidelineswereusedtoidentifypreviouslyidentiÞedimpactfulstudiesonthesetopics.AdditionalClinicalreportswerereviewedtoensureparityofexpertopinion(AAPandICON).AdditionalPubMedsearcheswereperformedprimarilytoidentifyitemsintheliteratureafterSeptember2009thatwerepertinenttoupdatethesetopics.Meta-analyseswerealwaysselectedwhenavailable.Gradingofeachreferencewasperformedasapplicable(seethereferencelist),andoverallgradesandstrengthsofrecommendationswereplacedafterthesummarystatements.Searchtermsincludefoodallergy,foodallergen,andeachofthespeciÞcconditionsreviewedinthisparameter.SUMMARYSTATEMENTSSummaryStatement1:Evaluatethepatientforpossiblefoodal-lergywiththeunderstandingthatarelativelysmallnumberofal-lergenscauseahighproportionoffoodallergy(eg,cowÕsmilk,henÕsegg,soy,wheat,peanut,treenuts,Þsh,andshellÞsh).SeeSummaryStatement48formanagement.[Strengthofrecommen-dation:Strong;BEvidence]SummaryStatement2:AdvisepatientswhoareallergictocertainspeciÞcfoodsabouttheriskofingestionofsimilarcross-reactingfoods.Examplesincludeingestionofothertreenutsinpatientswithtreenutallergy(eg,walnutandpecanorpis-tachioandcashew),Crustaceainpatientswithcrustaceanseafoodallergy,vertebrateÞshinpatientswithÞshallergy,andothermammalianmilksinpatientswithcowÕsmilkallergy.[Strengthofrecommendation:Strong;CEvidence] (Continued)WorkgroupmemberDisclosuresBrianP.Vickery,MDCephalonÐResearchgrantThrasherResearchFundÐResearchgrantWallaceResearchFoundationÐResearchgrantAmericanCollegeofAllergy,Asthma&ImmunologyÐGrantAmericanLungAssociationÐGrant/SteeringCommitteeMemberNIH/NIAIDÐGrantRobertWood,MDFAREÑMedicalAdvisoryBoardAllergyandAsthmaFoundationofAmericaÐConsultantNIHÐResearchsupportAmericanBoardofAllergyandImmunologyÐBoardofDirectorsAmericanBoardofPediatricsÐBoardofDirectorsAmericanAcademyofAllergy,Asthma&Immunology(AAAAI)ÐBoardofDirectorsJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL SummaryStatement3:Avoidothermammalianmilks,suchasgoatÕsmilkorsheepÕsmilk,inpatientswithcowÕsmilkallergybecauseofhighlycross-reactiveallergens.[Strengthofrecom-mendation:Strong;BEvidence]SummaryStatement4:Advisepatientswithseafoodallergythattheyarenotatincreasedriskofareactiontoradiocontrastmedia.ThereisnodocumentedrelationshipbetweennonÐIgE-mediatedanaphylacticreactionstoradiocontrastmediaandallergytoÞsh,crustaceanshellÞsh,oriodine.[Strengthofrecom-mendation:Strong;DEvidence]SummaryStatement5:TestforIgEantibodiesspeciÞcfortheimmunogenicoligosaccharidegalactose-alpha-1,3-galactose(alpha-gal)inpatientswhoreportadelayedsystemicreactiontoredmeatorunexplainedanaphylaxis,particularlyiftheyhaveahistoryofprevioustickbites.[Strengthofrecommenda-tion:Moderate;CEvidence]SummaryStatement6:Avoidallmammalianmeatsinpatientswithalpha-galallergybecausethisoligosaccharideantigeniswidelyexpressedinmammaliantissues.[Strengthofrecommen-dation:Moderate;CEvidence]SummaryStatement7:Evaluatepatientswithlatexallergyforthepossibilityofcross-reactivitytobanana,avocado,kiwi,chest-nut,potato,greenpepper,andotherfruitsandnuts.Individualizedmanagementisrecommendedbecauseclinicalreactionscausedbythiscross-reactivitycanrangefrommildtosevere.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement8:AdvisepatientsnottobeconcernedaboutingestinggeneticallymodiÞedfoodsgiventhecurrentstateofknowledgeandtheUSFoodandDrugAdministrationÕsscreeningrequirementstoruleoutallergenicityofgeneticallymodiÞedfoods.[Strengthofrecommendation:Weak;DSummaryStatement9:ManagenonÐIgE-mediatedreactionstofoodswithappropriateavoidanceandpharmacotherapyasindi-catedwiththeunderstandingthatthespeciÞcroleofimmunity(eg,IgA,IgM,IgG,andIgGsubclasses)intheseformsoffoodal-lergyhasnotbeendemonstrated.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement10:Determinewhetherthereportedhis-toryoffoodallergy,whichoftenprovesinaccurate,andlaboratorydataaresufÞcienttodiagnosefoodallergyorwhetheranoralfoodchallenge(OFC)isnecessary.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement11:ConsiderthenaturalcourseofallergiestospeciÞcfoodswhendecidingonthefrequencyoffoodallergyfollow-upevaluations,recognizingthatallergiestocertainfoods(milk,egg,wheat,andsoy)generallyresolvemorequicklyinchildhoodthanothers(peanut,treenuts,Þsh,andshellÞsh).Theseobservationscouldsupportindividualizedfollow-up(ie,roughlyyearlyre-evaluationsoftheseallergiesinchildhood)withlessfrequentretestingifresultsremainparticularlyhigh(eg,�20-50/L).[Strengthofrecommendation:Moderate;CEvidence]SummaryStatement12:Encourageexclusivebreast-feedingfortheÞrst4to6monthsoflife.[Strengthofrecommendation:Weak;CEvidence]SummaryStatement13:Forinfantswithafamilyhistoryofatopy,considerapartiallyorextensivelyhydrolyzedinfantfor-mulaforpossiblepreventionofatopicdermatitisandinfantcowÕsmilkallergyifexclusivebreast-feedingisnotpossible.[Strengthofrecommendation:Moderate;BEvidence]SummaryStatement14:DonotrecommendmaternalallergenavoidanceoravoidanceofspeciÞccomplementaryfoodsatweaningbecausetheseapproacheshavenotprovedeffectiveforprimarypreventionofatopicdisease.[Strengthofrecommenda-tion:Weak;CEvidence]SummaryStatement15:Donotroutinelyrecommendsupple-mentationofthematernalorinfantdietwithprobioticsorprebi-oticsasameanstopreventfoodallergybecausethereisinsufÞcientevidencetosupportabeneÞcialeffect.[Strengthofrecommendation:Weak;CEvidence]SummaryStatement16:Donotroutinelyrecommendthatpatientswithchronicidiopathicurticaria(CIU)avoidfoodscontainingadditives.[Strengthofrecommendation:Strong;BSummaryStatement17:Donotroutinelyinstructasthmaticpa-tientstoavoidsulÞtesorotherfoodadditivesunlesstheyhaveapriorreactiontosulÞtes.SulÞtesaretheonlyfoodadditiveprovedtotriggerasthma.Althoughthesereactionscanbesevere,evenlife-threateninginsensitivesubjects,theyarerare.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement18:Considernaturalfoodadditivesintheevaluationofpatientswithahistoryofunexplainedingestant-relatedanaphylaxis.[Strengthofrecommendation:Moderate;CSummaryStatement19:Patientswhoexperienceanadversere-actiontofoodadditivesshouldbeevaluatedforsensitivitytoannattoandcarmine.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement20:Cliniciansshouldbeawarethatavoid-ancemeasuresareappropriateforpatientswithhistoriescompat-iblewithadversereactionstoanadditiveuntildiagnosticevaluationcanbeperformed.[Strengthofrecommendation:Moderate;CEvidence]SummaryStatement21:Cliniciansshouldnotrecommendfoodadditiveavoidanceintheirpatientswithhyperactivity/attentiondeÞcitdisorder.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement22:Theclinicianshouldobtainadetailedmedicalhistoryandphysicalexaminationtoaidinthediagnosisoffoodallergy.[Strengthofrecommendation:Strong;DEvidence]SummaryStatement23:TheclinicianshouldusespeciÞcIgEtests(skinpricktests,serumtests,orboth)tofoodsasdiagnostictools;however,testingshouldbefocusedonfoodssuspectedofprovokingthereaction,andtestresultsaloneshouldnotbeconsidereddiagnosticoffoodallergy.[Strengthofrecommenda-tion:Strong;BEvidence]SummaryStatement24:Component-resolveddiagnostictestingtofoodallergenscanbeconsidered,asinthecaseofpea-nutsensitivity,butitisnotroutinelyrecommendedevenwithpea-nutsensitivitybecausetheclinicalutilityofcomponenttestinghasnotbeenfullyelucidated.[Strengthofrecommendation:Weak;CEvidence]SummaryStatement25:TheclinicianshouldconsiderOFCstoaidinthediagnosisofIgE-mediatedfoodallergy.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement26:Ifclinicalhistoryisnotconsistentwithanaphylaxis,performagradedOFCtoruleoutfoodallergy.Openfoodchallengeisbothcost-andtime-efÞcient.[Strengthofrecommendation:Moderate;CEvidence]JALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL SummaryStatement27:Ifthediagnosisisstillunclearafteropenfoodchallenge,thenrecommendablindfoodchallenge.[Strengthofrecommendation:Moderate;BEvidence]SummaryStatement28:EliminationdietsanddietdiariescanbeusedasanadjunctivemeanstodiagnosefoodallergiesbutarenottobedependedonsolelyforconÞrmingadiagnosis.[Strengthofrecommendation:Weak;DEvidence]SummaryStatement29:Adiagnosisoffood-dependent,exercise-inducedanaphylaxisshouldbeconsideredwheninges-tionofcausalfoodorfoodsandtemporallyrelatedexerciseresultinsymptomsofanaphylaxis.Theclinicianshouldrecognizethatsymptomsonlyoccurwithingestionofthecausalfoodorfoodsproximatetoexerciseandthatingestionofthefoodintheabsenceofexercisewillnotresultinanaphylaxis.[Strengthofrecommen-dation:Strong;BEvidence]SummaryStatement30:Theclinicianshouldconsiderthediag-nosisoforalallergysyndrome(pollen-foodallergy)andobtainspeciÞcIgEtestingtopollensinpatientswhoexperiencelimitedoropharyngealsymptomsafteringestionoffoodantigensthatcross-reactwithpollenantigens.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement31:AdiagnosisofIgE-mediatedcontacturticariashouldbeconsideredinpatientswithahistoryofimme-diateurticarialrashatthesiteofcontactwithafoodallergen.[Strengthofrecommendation:Weak;DEvidence]SummaryStatement32:DonotroutinelyobtaintotalserumIgElevelsforthediagnosisoffoodallergy.[Strengthofrecommenda-tion:Strong;CEvidence]SummaryStatement33:Donotperformintracutaneoustestingforthediagnosisoffoodallergy(seediscussion).[Strengthofrecommendation:Strong;BEvidence]SummaryStatement34:Unprovedtests,includingallergen-speciÞcIgGmeasurement,cytotoxicityassays,appliedkinesi-ology,provocationneutralization,andhairanalysis,shouldnotbeusedfortheevaluationoffoodallergy.[Strengthofrecommen-dation:Strong;CEvidence]SummaryStatement35:Althoughroutineuseofatopypatchtestsfordiagnosisoffoodallergyisnotrecommended,theuseoffoodatopypatchtestsinpatientswithpediatriceosinophilicesophagitis(EoE)havebeendemonstratedtobevaluableinas-sessingpotentialfoodtriggers.[Strengthofrecommendation:Moderate;CEvidence]SummaryStatement36:ThephysicianshouldusethepatientÕsmedicalhistory,responsetoatrialofeliminationofthesuspectedfood,andOFCtoestablishadiagnosisoffoodproteinÐinducedenterocolitissyndrome(FPIES).However,whenthehistoryindi-catesthatinfantsorchildrenhaveexperiencedhypotensiveepi-sodesormultiplereactionstothesamefood,adiagnosiscanbebasedonaconvincinghistoryandabsenceofsymptomswhenthecausativefoodiseliminatedfromthediet.[Strengthofrecom-mendation:Strong;BEvidence]SummaryStatement37:TheclinicianshouldbeawarethatagastrointestinalevaluationwithendoscopyandbiopsyisusuallynotrequiredforthediagnosisofFPIESandallergicproctocolitiswithsymptomsthatrespondtoeliminationoftheoffendingfoodandrecurwhenthefoodisreintroducedintothediet.[Strengthofrecommendation:Weak;CEvidence]SummaryStatement38:Measurementoffood-speciÞcIgGandantibodiesinserumarenotrecommendedforthediagnosisofnonÐIgE-mediatedfood-relatedallergicdisorders.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement39:Atrialoftwicedailyproteinpumpin-hibitor(PPI)therapyfor8weeksbeforediagnostictestingforEoEisrecommendedtoexcludegastroesophagealreßuxdisease(GERD)andPPI-responsiveesophagealinÞltrationofeosino-phils.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement40:ThediagnosisofEoEshouldbebasedonthepresenceofcharacteristicsymptomsandendoscopicfeaturesandthepresenceof15ormoreeosinophilsperhigh-powerÞeldquantiÞedbyapathologistusinghematoxylinandeosinstainingofesophagealbiopsyspecimensatlightmicroscopy.[Strengthofrecommendation:Strong;BSummaryStatement41:Eosinophilicgastroenteritis(EGE)shouldbeconsideredaconstellationofclinicalsymptomsincom-binationwithgastric,smallintestine,and/orlargeintestineinÞl-trationofeosinophilsatgreaterthanthereportednormalnumbersofgastricandintestinaleosinophils.[Strengthofrecom-mendation:Weak;DEvidence]SummaryStatement42:Prescribeatargetedallergenelimina-tiondietasthetreatmentforknownorstronglysuspectedfoodal-lergy.Educationaboutproperfoodpreparationandtherisksofoccultexposureisessential.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement43:Recommendconsultationwithanutri-tionistforgrowingchildreninwhomeliminationdietsmightaffectgrowth,aswellasthosepatientswithmultiplefoodal-lergies,poorgrowthparameters,orboth.Cliniciansmustbeawareofthenutritionalconsequencesofeliminationdietsandcertainmedications,suchasesomeprazole,especiallyingrowingchildren.SpeciÞcally,identifyingalternativedietarysourcesofcalciumandvitaminDiscriticalforpatientswithmilkallergy.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement44:ReviewrecognitionandtreatmentofIgE-mediatedfood-relatedallergicreactionswitheachpatientandcaregivers,asappropriate.Emphasisshouldbeplacedonpromptawarenessofanaphylaxisandswiftintervention.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement45:Discussself-caremanagementtech-niques,especiallywithhigh-riskpatients,(eg,adolescents,youngadults,andasthmaticpatients),focusingonriskreductionandrecognitionandtreatmentofanaphylaxis.[Strengthofrecom-mendation:Strong;CEvidence]SummaryStatement46:UseepinephrineasÞrst-linemanage-mentforthetreatmentofanaphylaxis.[Strengthofrecommenda-tion:Strong;CEvidence]SummaryStatement47:Ensurethatself-injectableepinephrineisreadilyavailabletothepatientandinstructthepatient,care-giver,orbothontheimportanceofitsuseandself-administration,asrelevant.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement48:Evaluatechildrenwithfoodallergiesatregularintervals(1-2years),accordingtothepatientÕsageandthefoodallergen,todeterminewhetherheorsheisstillallergic.Iffoodallergyisunlikelytochangeovertime,asinadults,periodicre-evaluation(2-5years)isrecommended,dependingonthefoodallergy.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement49:Forpatientswithfood-dependent,exercise-inducedanaphylaxis,avoidfoodingestionwithin2to4hoursofexerciseforpreventionofsymptoms,andprovideprompttreatmentwithonsetofsymptoms.[Strengthofrecom-mendation:Strong;CEvidence]JALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL SummaryStatement50:Managepollen-foodallergysyndromeororalallergysyndromebydietaryavoidanceofrawfruits,veg-etables,orbothbasedonthepatientÕssymptomproÞleseverity.Theextentoffoodavoidancedependsontheseverityoforopha-ryngealsymptoms.[Strengthofrecommendation:Strong;CSummaryStatement51:Theclinicianshouldunderstandthevariousclinicalpresentationsoftheseconditions(ie,FPIES/proctocolitis/enteropathy),educatepatientsandcareprovidersaboutcommonfoodtriggers,andrecommendstrictfoodavoidanceofallergenicfoodsforsymptommanagement.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement52:UsevolumereplacementtherapyfortheacutecaremanagementofpatientswithFPIES.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement53:SeepatientswithFPIESandallergicgastrointestinaldisordersatregularintervalsandconsiderrechal-lengeinanappropriatemedicalfacilitybasedonthenaturalhis-toryofthespeciÞcdisorder.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement54:ConsiderserialtissuebiopsiesaspartofdiseasemanagementinpatientswithEoE.SymptomsaloneorendoscopywithoutbiopsycannotbeusedasanaccurategaugeofEoEdiseaseactivity.[Strengthofrecommendation:Strong;CSummaryStatement55:ConsiderassessmentforaeroallergensensitizationbecauseEoEcanbetriggeredbyaeroallergensinhu-mansubjectsandanimalmodelsandtheremightbeaseasonalitytoEoEdiagnoses.[Strengthofrecommendation:Moderate;DSummaryStatement56:ConsiderfoodallergyevaluationwithbothskinprickandpatchtestingforEoEtoruleoutpossiblefoodtriggers.RememberthatpositiveserumspeciÞcIgElevels,foodskinpricktestresponses,andfoodpatchtestresultsarenotsufÞ-cienttodiagnosefoodtriggersforEoE.[Strengthofrecommen-dation:Moderate;CEvidence]SummaryStatement57:Considertheuseoftargetedorempiricfood-eliminationdietsoraminoacidÐbaseddietsforsuccessfulEoEtherapy.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement58:ConsidertheuseofswallowedtopicalesophagealcorticosteroidsforsuccessfulEoEtherapy.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement59:Referraltoagastroenterologistforesophagealdilationisrecommendedforhigh-gradestenosisbutdoesnotprovideinßammatorycontrol.[Strengthofrecommen-dation:Moderate;CEvidence]SummaryStatement60:AdministeroralcorticosteroidsforEGEasthepreferredtherapy.[Strengthofrecommendation:Weak;CEvidence]SummaryStatement61:Althoughimmunotherapeuticap-proaches,suchasoralimmunotherapy,inclinicaltrialsshowpromiseintreatingfoodallergy,theyarenotreadyforimplementationinclinicalpracticeatthepresenttimebecauseofinadequateevidencefortherapeuticbeneÞtoverrisksoftherapy.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement62:Developawrittenactionplanfortreat-mentofallergicreactionstofoodforadultsandchildren.[Strengthofrecommendation:Moderate;DEvidence]SummaryStatement63:Inquireaboutandaddressbehavioralchangesbecauseofbullyinginpatientswithfoodallergy.Thisinquiryshouldincludeadultsandchildren.[Strengthofrecom-mendation:Strong;DEvidence]SummaryStatement64:Teachpatientsthatingestion,ratherthancasualexposurethroughtheskinorcloseproximitytoanallergen,isalmosttheonlyroutefortriggeringsevereallergic/anaphylacticreactions.[Strengthofrecommendation:Strong;CPREFACEAsdeÞnedbytheNIAIDexpertpanel,foodallergyisdeÞnedhereÔÔasanadversehealtheffectarisingfromaspeciÞcimmuneresponsethatoccursreproduciblyonexposuretoagivenfood.ÕÕHere,thetermallergyisnotlimitedtoIgE-mediatedimmuno-logicreactionsandisusedtoconnotetheinductionofclinicalsignsandsymptoms,asopposedto,whichindicatesthepresenceofIgEantibodiestoafood,oftenintheabsenceofclinicalsymptomatology.AlthoughtheprevalenceoffoodallergyoverallandofallergytospeciÞcfoodsisuncertainbecausestudiesvaryinmethodologicalapproaches,allergistswhohavebeeninpracticeforatleastadecadehavebeenconfrontedwithanever-growingnumberofpatientswithfoodallergy.Onthebasisofarecentextensivereviewoftheliterature,foodallergyisestimatedtoaffectmorethan1%to2%andlessthan10%oftheTherearelimiteddatatosuggestthatfoodallergyprevalencehasincreased,butnationalsurveyssuggestthatpeanutallergyhastripledsincethelate1990s.Inconsideringanumberofpublishedstudies,itisapparentthatestimatesoffoodal-lergyprevalencearehighestwhenbasedonself-report(approxi-mately12%to13%)comparedwithestimatesbasedonstudiesusingtests,suchasOFCs(approximately3%).Thisobservationregardingadiscordanceofsuspectedandprovedfoodallergyun-derscorestheimportanceofusingproveddiagnosticmethodstoevaluateindividualpatientssuspectedofahavingfoodallergy.Thephysicianshouldapplyinformationregardingepidemio-logicfeaturesoffoodallergywhenapproachingdiagnosisandmanagement,recognizingthatself-reportedfoodallergyismorecommonthanprovedfoodallergy,thatfoodallergyismorecommoninchildren,thatalimitednumberoffoodsaccountformostsigniÞcantfoodallergies,andthatfoodallergyoccursmorecommonlyinpersonswithotheratopicdiseases.Thereareanumberofepidemiologicfeaturesregardingfoodallergythatmightbehelpfulinconstructingaprioriassessmentofriskandconsiderationofpotentialtriggerswhenevaluatingindividualpa-tients.Althoughmorethan170foodshavebeenidentiÞedastrig-gersoffoodallergy,thosecausingmostofthesigniÞcantallergicreactionsincludepeanut,treenuts,Þsh,shellÞsh,milk,egg,wheat,soy,andseeds.Foodallergy(tofoodsotherthanshellÞshandfruits/vegetables)ismorecommoninchildrenthaninadults.Asdescribedelsewhereinthisparameter,milk,egg,wheat,andsoyallergiesaremorecommoninchildrenthaninadults.Thereisahighco-occurrenceoffoodallergywithotheratopicdiseases,includingatopicdermatitis,asthma,andallergicInparticular,childrenwithmoderate-to-severeatopicdermatitisappeartohaveasigniÞcantrisk(approximately35%)offoodallergy.Therearenosimilarstudiesinadults,andthereforetheprevalenceofco-occurringfoodallergyinadultswithatopicdermatitisisunknown.CutaneousreactionstofoodsaresomeofthemostcommonpresentationsoffoodallergyandincludeIgE-mediated(urticaria,JALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL angioedema,ßushing,andpruritus),cell-mediated(contactdermatitisanddermatitisherpetiformis),andmixedIgE-andcell-mediated(atopicdermatitis)reactions.ThesearedeÞnedasfollows:AcuteurticariaisacommonmanifestationofIgE-mediatedfoodallergy,althoughfoodallergyisnotthemostcommoncauseofacuteurticariaandisrarelyacauseofchronicur-Urticariaisthemostcommonsymptominpatientsexperiencingfood-inducedanaphylaxis.Angioedemamostoftenoccursincombinationwithurti-cariaand,iffoodinduced,istypicallyIgEmediated.gioedemaisalsoacommonsymptominpatientswithAtopicdermatitis/atopiceczemaislinkedtoacomplexinteractionbetweenskinbarrierdysfunctionandenviron-mentalfactors,suchasirritants,microbes,andaller-InsomesensitizedpatientsfoodallergensmightbesigniÞcanttriggersforatopicdermatitis/atopiceczema,especiallyininfantsandyoungchildren,inwhomfoodal-lergensareestimatedtobeasigniÞcanttriggerin30%to40%ofpatients.Allergiccontactdermatitisisaformofeczemacausedbycell-mediatedallergicreactionstochemicalhaptenspresentinsomefoods,eithernaturally(eg,mango)orasaddi-tives.Clinicalfeaturesincludemarkedpruritus,erythema,papules,vesicles,andedema.ContacturticariacausedbyfoodallergyisanIgE-mediatedreactioncausedbydirectskincontactinasensitizedsub-jects.Althoughcommon,reactionsaretypicallynotsevereandconÞnedonlytothesiteofcontact.Gastrointestinalreactionsarealsoafrequentmanifestationoffoodallergy.However,thefrequencyandunpredictabilityofanaphylaxiscausethemostanxietyinpatientsandtheirfamilies.Theincidenceoffood-inducedanaphylaxisisunclear.The5USstudiesthathavebeenconductedtoestimatetheprevalenceoffood-inducedanaphylaxishavefoundwidedifferencesintheratesofhospitalizationoremergencydepartmentvisitsforanaphylaxis,asassessedbyInternationalClassiÞcationofDiseasescodesormedicalrecordreview,from1/100,000popu-lationtoashighas70/100,000population.Theproportionofanaphylaxiscasesthoughttobeduetofoodsinthesestudiesalsovariedwidely,rangingfrom13%to65%,withthelowestpercent-agesfoundinthosestudieswithmorestringentdiagnosticcriteriaforanaphylaxis.Onestudyreportedthatthenumberofhospital-izationsforanaphylaxisincreasedwithincreasingage,whereasanotherstudyreportedtotalcasesofanaphylaxiswerealmosttwiceashighinchildrenasinadults.Thesevariationsmightbeduetodifferencesinstudymethodsordifferencesinpopulationsstudied.Althoughitisestimatedthatgreaterthan12millionAmericanshavefoodallergies,datafromtheUSFoodandDrugAdministrationÕsNationalElectronicInjurySurveillanceSystemofemergencydepartmentencounterssuggestabout125,000visitsperyearforfood-inducedallergicreactions,14,000visitsperyearforfood-inducedanaphylaxis,andapprox-imately3,100hospitalizationsperyearrelatedtofoodallergy.Fatalitiesarerareandestimatedtobelessthan100peryear,withthemajorityoccurringduringthesecondthroughfourthde-cadesoflife.ToreadthePracticeParameterinitsentirety,pleasedownloadtheonlineversionofthisarticlefromwww.jacionline.orgwww.jcaai.org,orwww.allergyparameters.org.Pleasenotethatallref-erencescitedintheExecutiveSummarycanbefoundintheonlinedocument.Thereaderisreferredtotheonlineportionofthedocu-mentformoredetaileddiscussionofthecommentsmadeintheprintedversion.JALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL Foodallergy:Apracticeparameterupdate—2014HughA.Sampson,MD,SeemaAceves,MD,PhD,S.AllanBock,MD,JohnJames,MD,StacieJones,MD,DavidLang,MD,KariNadeau,MD,PhD,AnnaNowak-Wegrzyn,MD,JohnOppenheimer,MD,TamaraT.Perry,MD,ChristopherRandolph,MD,ScottH.Sicherer,MD,RonaldA.Simon,MD,BrianP.Vickery,MD,andRobertWood,MDChiefEditors:HughA.Sampson,MD,andChristopherRandolph,MDMembersoftheJointTaskForceonPracticeParameters:DavidBernstein,MD,JoannBlessing-Moore,MD,DavidKhan,MD,DavidLang,MD,RichardNicklas,MD,JohnOppenheimer,MD,JayPortnoy,MD,ChristopherRandolph,MD,DianeSchuller,MD,SheldonSpector,MD,StephenA.Tilles,MD,andDanaWallace,MDPracticeParameterWorkgroup:HughA.Sampson,MD(Chair),SeemaAceves,MD,PhD,S.AllanBock,MD,JohnJames,MD,StacieJones,MD,DavidLang,MD,KariNadeau,MD,PhD,AnnaNowak-Wegrzyn,MD,JohnOppenheimer,MD,TamaraT.Perry,MD,ChristopherRandolph,MD,ScottH.Sicherer,MD,RonaldA.Simon,MD,BrianP.Vickery,MD,andRobertWood,MDThisparameterwasdevelopedbytheJointTaskForceonPracticeParameters,representingtheAmericanAcademyofAllergy,Asthma&Immunology(AAAAI);theAmericanCollegeofAllergy,Asthma&Immunology(ACAAI);andtheJointCouncilofAllergy,Asthma&Immunology(JCAAI).TheAAAAIandtheACAAIhavejointlyacceptedresponsibilityforestablishing‘‘FoodAllergy:Apracticeparameterupdate—2014.’’Thisisacompleteandcomprehensivedocumentatthecurrenttime.Themedicalenvironmentisachangingone,andnotallrecommendationswillbeappropriateforallpatients.Becausethisdocumentincorporatedtheeffortsofmanyparticipants,nosingleindividual,includingthosewhoservedontheJointTaskForce,isauthorizedtoprovideanofcialAAAAIorACAAIinterpretationofthesepracticeparameters.AnyrequestforinformationaboutoraninterpretationofthesepracticeparametersbytheAAAAIorACAAIshouldbedirectedtotheExecutiveOfcesoftheAAAAI,ACAAI,andJCAAI.Theseparametersarenotdesignedforusebypharmaceuticalcompaniesindrugpromotion.Keywords:Foodallergy,foodallergen,cross-reactivity,adversefoodreactions,IgE-mediatedfoodallergy,eosinophilicesophagitisPreviouslypublishedpracticeparametersoftheJointTaskForceonPracticeParametersforAllergyandImmunologyareavailableathttp://www.JCAAI.orghttp://www.allergyparameters.orgCONTRIBUTORSTheJointTaskForcehasmadeaconcertedefforttoacknowledgeallcontributorstothisparameter.Ifanycontributorshavebeenexcludedinadvertently,theTaskForcewillensurethatappropriaterecognitionofsuchcontributionsismadesubsequently. Disclosureofpotentialconßictofinterest:H.A.SampsonhasreceivedresearchsupportfromtheNationalInstituteofAllergyandInfectiousDisease(NIAID;AI44236andAI66738),theNationalInstitutesofHealth(NIH;RR026134),andFoodAllergyResearchandEducation(FARE);hasreceivedtravelsupportasthechairofPhARFAwardreviewcommittee;hasconsultantarrangementswithAllerteinTherapeutics,Regeneron,andtheDanoneResearchInstitute;andhasreceivedpaymentforlecturesfromThermoFisherScientiÞc,UCB,andPÞzer.S.AcevesisamemberofthemedicaladvisorypanelfortheAmericanPartnershipforEosinophilicDisorders;hasreceivedresearchsupportfromtheNIH(NIAIDAI092135),theDepartmentofDefense,andtheAmericanAcademyofAllergy,Asthma&Immunology(AAAAI)/AmericanPartner-shipforEosinophilicDisorders;hasapatentheldbyUniversityofCaliforniaÐSanDiegoforOVBlicensedtoMeritagePharma;andhasreceivedtravelsupportfromtheNIHandtheFalkFoundation.S.A.BockisonthemedicaladvisoryboardforFARE.S.JoneshasreceivedresearchsupportfromtheNIH(COFAR),theNIH/NIAIDImmuneToleranceNetwork(A1-15416),andFARE.D.LangisaspeakerforGenentech/Novartis,GlaxoSmithKline,andMerck;hasconsultantarrangementswithGlaxoSmithKline,Merck,Aerocrine;andhasreceivedresearchsupportfromGenentech/NovartisandMerck.A.Nowak-WegrzynisaspeakerforThermoFisherScientiÞc,isontheadvisoryboardforNutricia,isontheDataSafetyMonitoringBoardforMerck,andhasreceivedresearchsupportfromNestle(grant0955),Nutricia,andtheNIH.J.OppenheimerhasreceivedresearchsupportfromAstraZeneca,GlaxoSmithKline,Merck,BoehringerIngelheim,Novartis,andMedImmune;hasprovidedlegalconsultation/expertwitnesstestimonyinmalpracticedefensecases;ischairmanoftheAmericanBoardofAllergyandImmunology;andhasconsultantarrangementswithGlaxoSmithKline,Mylan,Novartis,andSunovion.C.RandolphisamemberoftheBoardofRegentsfortheAmericanCollegeofAllergy,Asthma&Immunology(ACAAI);hasconsultantarrangementswithAstraZenecaandGenentech;hasreceivedpaymentforlecturesfromGlaxoSmithKline,AstraZeneca,Genentech,andTEVA;andhasreceivedtravelsupportfromTEVA.S.H.SichererhasreceivedresearchsupportfromtheNIAID,isamemberoftheAmericanBoardofAllergyandImmunology,hasconsultantarrangementswithNovartisandFARE;andreceivesroyaltiesfromUpToDate.R.A.SimonhasprovidedexperttestimonyforvariouslawÞrms;hasreceivedpaymentforlecturesfromMerck,Novartis,andCSL-Behring;holdspatentsfortheuseofsurfactantsinchronicrhinosinusitisandasthma;hasreceivedroyaltiesfromWileyBlackwellandUpToDate;andhasstockoptionsinURXmobile.B.P.VickeryhasreceivedresearchsupportfromtheNIH/NIAID(AI099083)andtheFoundationoftheACAAI.R.WoodhasconsultantarrangementswiththeAsthmaandAllergyFoundationofAmerica,isemployedbyJohnsHopkinsUniversity,hasreceivedresearchsupportfromtheNIH,andreceivesroyaltiesfromUpToDate.Therestoftheauthorsdeclarethattheyhavenorelevantconßictsofinterest.WethankAnneMunoz-FurlongforreviewandhelpfulcommentstoÔÔSectionIX:Managementinspecialsettings.ÕÕReceivedforpublicationFebruary7,2014;revisedMay2,2014;acceptedforpublicationMay6,2014.AvailableonlineAugust28,2014.Correspondingauthor:SusanL.Grupe,JointTaskForceonPracticeParameters,50NBrockwaySt,#304,Palatine,IL60067.E-mail:grupes@jcaai.org0091-6749/$36.002014AmericanAcademyofAllergy,Asthma&Immunologyhttp://dx.doi.org/10.1016/j.jaci.2014.05.013JALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL WORKGROUPCHAIRHughA.Sampson,MDJaffeFoodAllergyInstituteDepartmentofPediatricsIcahnSchoolofMedicineatMountSinaiNewYork,NewYorkJOINTTASKFORCELIAISONChristopherRandolphDepartmentofPediatrics/Allergy/ImmunologyYaleAfÞliatedHospitalsCenterforAllergy,Asthma,&ImmunologyWaterbury,ConnecticutJOINTTASKFORCEMEMBERSDavidI.Bernstein,MDDepartmentsofClinicalMedicineandEnvironmentalDivisionofAllergy/ImmunologyUniversityofCincinnatiCollegeofMedicineCincinnati,OhioJoannBlessing-Moore,MDDepartmentsofMedicineandPediatricsStanfordUniversityMedicalCenterDepartmentofImmunologyPaloAlto,CaliforniaDavidA.Khan,MDDepartmentofInternalMedicineUniversityofTexasSouthwesternMedicalCenterDallas,TexasDavidM.Lang,MDAllergy/ImmunologySectionRespiratoryInstituteAllergyandImmunologyFellowshipTrainingProgramClevelandClinicFoundationCleveland,OhioRichardA.Nicklas,MDDepartmentofMedicineGeorgeWashingtonMedicalCenterWashington,DCJohnOppenheimer,MDDepartmentofInternalMedicineNewJerseyMedicalSchoolPulmonaryandAllergyAssociatesMorristown,NewJerseyJayM.Portnoy,MDSectionofAllergy,Asthma&ImmunologyChildrenÕsMercyHospitalDepartmentofPediatricsUniversityofMissouriÐKansasCitySchoolofMedicineKansasCity,MissouriDianeE.Schuller,MDDepartmentofPediatricsPennsylvaniaStateUniversityMiltonS.HersheyMedicalCollegeHershey,PennsylvaniaSheldonL.Spector,MDDepartmentofMedicineUCLASchoolofMedicineLosAngeles,CaliforniaStephenA.Tilles,MDDepartmentofMedicineUniversityofWashingtonSchoolofMedicineRedmond,WashingtonDanaWallace,MDDepartmentofMedicineNovaSoutheasternUniversityCollegeofOsteopathicDavie,FloridaPARAMETERWORKGROUPMEMBERSSeemaAceves,MD,PhDEosinophilicGastrointestinalDisordersClinicDivisionofAllergy,ImmunologyDepartmentsofPediatricsandMedicineUniversityofCalifornia,SanDiegoRadyChildrenÕsHospitalSanDiego,CaliforniaS.AllanBock,MDDepartmentofPediatricsNationalJewishHealthDenver,ColoradoDepartmentofPediatricsUniversityofColoradoSchoolofMedicineAurora,ColoradoJohnM.James,MDPrivateClinicalPracticeColoradoAllergyandAsthmaCenters,PCFortCollins,ColoradoJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL StacieJones,MDDepartmentofPediatricsAllergyandImmunologyUniversityofArkansasforMedicalSciencesArkansasChildrenÕsHospitalLittleRock,ArkansasDavidM.Lang,MDAllergy/ImmunologySectionDivisionofMedicineAllergyandImmunologyFellowshipTrainingClevelandClinicFoundationCleveland,OhioKariNadeau,MD,PhDDepartmentofAllergy,AsthmaandImmunologyStanfordUniversitySchoolofMedicineStanford,CaliforniaAnnaNowak-Wegrzyn,MDDepartmentofPediatricsJaffeFoodAllergyInstituteDivisionofAllergyandImmunologyIcahnSchoolofMedicineatMountSinaiNewYork,NewYorkJohnOppenheimer,MDDepartmentofInternalMedicineNewJerseyMedicalSchoolPulmonaryandAllergyAssociatesMorristown,NewJerseyTamaraT.Perry,MDDepartmentofPediatricsAllergyandImmunologyDivisionUniversityofArkansasforMedicalSciencesArkansasChildrenÕsHospitalLittleRock,ArkansasScottH.Sicherer,MDDepartmentofPediatricsPediatricAllergyandImmunologyIcahnSchoolofMedicineatMountSinaiJaffeFoodAllergyInstituteNewYork,NewYorkRonaldA.Simon,MDDivisionofAllergy,Asthma&ImmunologyScrippsClinicDepartmentofExperimental&MolecularMedicineScrippsResearchInstituteLaJolla,CaliforniaBrianP.Vickery,MDDepartmentofPediatricsUniversityofNorthCarolinaSchoolofMedicineChapelHill,NorthCarolinaRobertWood,MDDepartmentofPediatricsandInternationalHealthDivisionofPediatricAllergyandImmunologyJohnsHopkinsUniversitySchoolofMedicineBaltimore,MarylandTABLEOFCONTENTSI.ClassiÞcationofmajorfoodallergens,cross-reactivities,geneticallymodiÞedfoods,andclinicalimplicationsA.ClassiÞcationB.Cross-reactivityC.GeneticallymodiÞedorganismsinfoodsandthepotentialforallergenicityII.MucosalimmuneresponsesinducedbyfoodsIII.TheclinicalspectrumoffoodallergyA.CategoriesofadversefoodreactionsB.DeÞnitionsofspeciÞcfood-inducedallergicIV.Prevalence,naturalhistory,andpreventionA.NaturalhistoryB.PreventionoffoodallergyV.AdversereactionstofoodadditivesVI.Diagnosisoffoodallergy,differentialdiagnosis,anddiag-nosticalgorithmA.DiagnosisofIgE-mediatedfoodallergyB.Non-IgEmediated:FPIES,allergicproctocolitis,andC.EosinophilicesophagitisD.EosinophilicgastroenteritisVII.Managementoffoodallergyandfood-dependent,exercise-inducedanaphylaxisVIII.EmergingtherapiesforfoodallergyIX.ManagementinspecialsettingsJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL CLASSIFICATIONOFRECOMMENDATIONSANDEVIDENCERecommendationratingscaleCategoryofevidenceIaEvidencefrommeta-analysisofrandomizedcontrolledIbEvidencefromatleast1randomizedcontrolledtrialIIaEvidencefromatleast1controlledstudywithoutIIbEvidencefromatleast1othertypeofquasiexperimentalIIIEvidencefromnonexperimentaldescriptivestudies,suchascomparativestudiesIVEvidencefromexpertcommitteereportsoropinionsorclinicalexperienceofrespectedauthoritiesorbothStrengthofrecommendation*ADirectlybasedoncategoryIevidenceBDirectlybasedoncategoryIIevidenceorextrapolatedrecommendationfromcategoryIevidenceCDirectlybasedoncategoryIIIevidenceorextrapolatedrecommendationfromcategoryIorIIevidenceDDirectlybasedoncategoryIVevidenceorextrapolatedrecommendationfromcategoryI,II,orIIIevidenceLBLaboratorybasedNRNotratedSUMMARYOFCONFLICTOFINTERESTDISCLOSURESThefollowingisasummaryofinterestsdisclosedonwork-groupmembersÕconßictofinterestdisclosurestatements(notincludinginformationconcerningfamilymemberinterests).Completedconßictofinterestdisclosurestatementsareavailableonrequest. StatementStrongrecommendation(StrRec)AstrongrecommendationmeansthebeneÞtsoftherecommendedapproachclearlyexceedtheharms(orthattheharmsclearlyexceedthebeneÞtsinthecaseofastrongnegativerecommendation)andthatthequalityofthesupportingevidenceisexcellent(gradeAorB).*InsomeclearlyidentiÞedcircumstances,strongrecommendationsmightbemadebasedonlesserevidencewhenhigh-qualityevidenceisimpossibletoobtainandtheanticipatedbeneÞtsstronglyoutweightheCliniciansshouldfollowastrongrecommendationunlessaclearandcompellingrationaleforanalternativeapproachispresent.Moderate(Mod)ArecommendationmeansthebeneÞtsexceedtheharms(orthattheharmsexceedthebeneÞtsinthecaseofanegativerecommendation),butthequalityofevidenceisnotasstrong(gradeBorC).*InsomeclearlyidentiÞedcircumstances,recommendationsmightbemadebasedonlesserevidencewhenhigh-qualityevidenceisimpossibletoobtainandtheanticipatedbeneÞtsoutweightheharms.Cliniciansshouldalsogenerallyfollowarecommendationbutshouldremainalerttonewinformationandsensitivetopatientpreferences.Weak(Weak)Anoptionmeansthateitherthequalityofevidencethatexistsissuspect(gradeD)*orthatwell-donestudies(gradeA,B,orC)*showlittleclearadvantagetooneapproachversusanother.Cliniciansshouldbeßexibleintheirdecisionmakingregardingappropriatepractice,althoughtheymightsetboundsonalternatives;patientpreferenceshouldhaveasubstantialinßuencingrole.Norecommendation(NoRec)Norecommendationmeansthereisbothalackofpertinentevidence(gradeD)*andanunclearbalancebetweenbeneÞtsandharms.CliniciansshouldfeellittleconstraintintheirdecisionmakingandbealerttonewpublishedevidencethatclariÞesthebalanceofbeneÞtversusharm;patientpreferenceshouldhaveasubstantialinßuencingrole. WorkgroupmemberDisclosuresHughA.Sampson,MDAllerteinTherapeuticsÐConsultantFoodAllergyResearchandEducation(FARE)ÐMedicalAdvisoryBoard,unpaidNovartisÐConsultant,unpaidDBVScientiÞcAdvisoryBoard,unpaidThermoFisherScientiÞcÐEAACItravelexpensesandhonorariumUCBÐXXNationalCongressoftheMexicanPediatricSpecialistsinClinicalImmunologyandAllergyÐTravelexpensesandhonorariumNationalInstituteofAllergyandInfectiousDiseases(NIAID)ÐResearchgrantFAREÐResearchgrantUniversityofNebraska(FARRP)ÐConsultantAllergyandAsthmaFoundationofAmericaÐConsultantJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL WorkgroupmemberDisclosuresSeemaAceves,MD,PhDMeritagePharmaÐPatentroyaltiesS.AllanBock,MDFoodAllergyandAnaphylaxisNetworkÑMedicalAdvisoryBoardNationalJewishHealthÐResearchafÞliateJohnJames,MDAmericanBoardofAllergyandImmunologyÐMedicalAdvisoryBoardParentsofAsthmaticandAllergicChildrenÐMedicalAdvisoryBoardStacieJones,MDNationalInstitutesofHealth(NIH)/NIAIDÐResearchgrantNationalPeanutBoardÐResearchgrantFAREÐAdvisoryboard;researchgrantSanoÞ-AventisÐSteeringCommitteeMemberNIAIDSafetyMonitoringCommitteeÐGrantreviewNIAIDStudySectionÐAdHocReviewAAAAIÐSpeakerIndianaUniversityMedicalSchoolandRileyChildrenÕsHospitalÐSpeakerSpanishSocietyofAllergy&ClinicalImmunology(SEAIC),Madrid,SpainÐSpeakerOregonAllergy,Asthma&ImmunologySocietyÐSpeakerDavidLang,MDTeraÐSpeakerSanoÞ-AventisÐAdvisoryBoardMerckÐAdvisoryBoard;speakerAstra-ZenecaÐSpeakerGenentechÐSpeakerGlaxoSmithKlineÐSpeakerGenentech/NovartisÐResearchgrantKariNadeau,MD,PhDNIAIDÐResearchgrantFAREÐResearchgrantAnnaNowak-Wegrzyn,MDMerckÐAdvisoryBoardFAREÐGrantNestleÐGrantNewYorkAllergyandAsthmaSocietyÐExecutiveCommitteeMemberJohnOppenheimer,MDTamaraT.Perry,MDNIH/NHLBIÐResearchgrantNIH/NIAIDÐResearchgrantNIHNationalCenterforMinorityHealthDisparitiesÐResearchgrantARCenterforClinicalandTranslationResearchÐResearchgrantChristopherRandolph,MDGlaxoSmithKlineÐConsultant;speaker;honorarium;researchgrantAstraÐConsultant;AdvisoryBoard;speaker;honorarium;researchgrantMerck-Consultant;speaker;honorarium;researchgrantGenentech/Novartis-Consultant;speaker;honorarium;researchgrantBaxterÐSpeakerDyaxÐResearchgrantDeyÐSpeakerAlcon-Speaker;honorarium;researchgrantISTA(Bepreve)ÐSpeaker;honorariumSunovion(Sepracor)ÐSpeakerCSFBehringÐSpeakerPharmaxisÐProvidedadvertisementTEVAÐSpeaker;researchgrantConnecticutAllergySocietyÐOfÞcerScottH.Sicherer,MDAmericanAcademyofPediatricsÐOfÞcerAmericanBoardofAllergyImmunologyÐBoardMemberAAAAIÐSpeakerJournalofAllergyandClinicalImmunologyJACI-InPracticeÐAssociateEditorNIH/NIAIDÐGrantsFAREÐConsultantFoodAllergyResearchandEducationÐMedicaladvisor/consultantNovartis-ConsultantRonaldA.Simon,MDNovartisÐSpeakersÕbureauNovartisÐResearchsupportMerckÐSpeakersÕbureauGlaxoSmithKlineÐSpeakersÕbureau(Continued)JALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL ResolutionofnondisqualifyinginterestsTheJointTaskForcerecognizesthatexpertsinaÞeldarelikelytohaveintereststhatcouldcomeintoconßictwithdevelopmentofacompletelyunbiasedandobjectivepracticeparameter.AprocesshasbeendevelopedtopreventpotentialconßictsfrominßuencingtheÞnaldocumentinanegativewaytotakeadvantageofthatexpertise.Attheworkgrouplevel,memberswhohaveapotentialconßictofinteresteitherdonotparticipateindiscussionsconcerningtopicsrelatedtothepotentialconßict,oriftheydowriteasectiononthattopic,theworkgroupcompletelyrewritesitwithouttheirinvolvementtoremovepotentialbias.Inaddition,theentiredocumentisreviewedbytheJointTaskForce,andanyapparentbiasisremovedatthatlevel.Finally,thepracticeparameterissentforreviewbothbyinvitedreviewersandbyanyonewithaninterestinthetopicbypostingthedocumentontheWebsitesoftheACAAIandAAAAI.ThepracticeparameteronfoodallergywaslastupdatedinandfocusedprimarilyonIgE-mediatedfoodallergy.Intheensuingyears,therehavebeenconsiderableadvancesintheÞeldinmanyareas,includingourbasicunderstandingoffoodallergens,diagnostictesting,nonÐIgE-mediateddisor-ders,andmanagementofvariousfood-inducedallergicreac-tions.In2010,theNIAIDÔÔGuidelinesonthediagnosisandmanagementoffoodallergyÕÕwerepublished,providingacomprehensivereviewofthescientiÞcliteratureandexpertopiniononfoodallergy.GiventhemanyadvancesintheÞeld,theJointTaskForceonPracticeParametersappointedaworkinggrouptoreviewandupdatethestandingpracticeparameters.TheworkinggroupreliedheavilyontheNIAIDGuidelinesandfocusedonadvancessincethepublicationofthatlandmarkdocument.THEJOINTTASKFORCEONPRACTICEPARAMETERSTheJointTaskForceonPracticeParameters(JTF)isa13-membertaskforceconsistingof6representativesassignedbytheAAAAI,6bytheACAAI,and1bytheJointCouncilofAllergyandImmunology.Thistaskforceoverseesthedevelopmentofpracticeparameters,selectstheworkgroupchairorchairs,andreviewsdraftsoftheparametersforaccuracy,practicality,clarity,andbroadutilityoftherecommendationsforclinicalpractice.FOODALLERGY:APRACTICEPARAMETERUPDATEÑ2014WORKGROUPTheFoodAllergy:APracticeParameterUpdate2014Work-groupwascommissionedbytheJTFtodevelopapracticeparameterthataddressesrecentadvancesintheÞeldoffoodallergyandtheoptimalmethodsofdiagnosisandmanagementbasedonanassessmentofthemostcurrentliterature.TheChair(HughA.Sampson,MD)invitedworkgroupmemberstoparticipateintheparameterdevelopmentwhoareconsideredtobeexpertsintheÞeldoffoodallergy.WorkgroupmembershavebeenvettedforÞnancialconßictofinterestbytheJTF,andtheirconßictsofinteresthavebeenlistedinthisdocumentandarepostedontheJTFWebsiteathttp://www.allergyparameters.orgThechargetotheworkgroupwastouseasystematicliteraturereviewinconjunctionwithconsensusexpertopinionandworkgroup-identiÞedsupplementarydocumentstodevelopapracticeparameterthatevaluatesthecurrentstateofthescienceregardingfoodallergy.PROTOCOLFORFINDINGEVIDENCETheNIAIDguidelineswereusedtoidentifypreviouslyidentiÞedimpactfulstudiesonthesetopics.AdditionalClinicalreportswerereviewedtoensureparityofexpertopinion(AAPandICON).AdditionalPubMedsearcheswereperformedpri-marilytoidentifyitemsintheliteratureafterSeptember2009thatwerepertinenttoupdatethesetopics.Meta-analyseswerealwaysselectedwhenavailable.Gradingofeachreferencewasper-formedasapplicable(seethereferencelist),andoverallgradesandstrengthsofrecommendationswereplacedafterthesummarystatements.Searchtermsincludefoodallergy,foodallergen,andeachofthespeciÞcconditionsreviewedinthisparameter.SUMMARYSTATEMENTSSummaryStatement1:Evaluatethepatientforpossiblefoodal-lergywiththeunderstandingthatarelativelysmallnumberofal-lergenscauseahighproportionoffoodallergy(eg,cowÕsmilk,henÕsegg,soy,wheat,peanut,treenuts,Þsh,andshellÞsh).SeeSummaryStatement48formanagement.[Strengthofrecommen-dation:Strong;BEvidence]SummaryStatement2:AdvisepatientswhoareallergictocertainspeciÞcfoodsabouttheriskofingestionofsimilarcross-reactingfoods.Examplesincludeingestionofothertreenutsinpatientswithtreenutallergy(eg,walnutandpecanor (Continued)WorkgroupmemberDisclosuresBrianP.Vickery,MDCephalonÐResearchgrantThrasherResearchFundÐResearchgrantWallaceResearchFoundationÐResearchgrantAmericanCollegeofAllergy,Asthma&ImmunologyÐGrantAmericanLungAssociationÐGrant/SteeringCommitteeMemberNIH/NIAIDÐGrantRobertWood,MDFAREÑMedicalAdvisoryBoardAllergyandAsthmaFoundationofAmericaÐConsultantNIHÐResearchsupportAmericanBoardofAllergyandImmunologyÐBoardofDirectorsAmericanBoardofPediatricsÐBoardofDirectorsAmericanAcademyofAllergy,Asthma&Immunology(AAAAI)ÐBoardofDirectorsJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL pistachioandcashew),Crustaceainpatientswithcrustaceansea-foodallergy,vertebrateÞshinpatientswithÞshallergy,andothermammalianmilksinpatientswithcowÕsmilkallergy.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement3:Avoidothermammalianmilks,suchasgoatÕsmilkorsheepÕsmilk,inpatientswithcowÕsmilkallergybecauseofhighlycross-reactiveallergens.[Strengthofrecom-mendation:Strong;BEvidence]SummaryStatement4:Advisepatientswithseafoodallergythattheyarenotatincreasedriskofareactiontoradiocontrastmedia.ThereisnodocumentedrelationshipbetweennonÐIgE-mediatedanaphylacticreactionstoradiocontrastmediaandallergytoÞsh,crustaceanshellÞsh,oriodine.[Strengthofrecom-mendation:Strong;DEvidence]SummaryStatement5:TestforIgEantibodiesspeciÞcfortheimmunogenicoligosaccharidegalactose--1,3-galactose(alpha-gal)inpatientswhoreportadelayedsystemicreactiontoredmeatorunexplainedanaphylaxis,particularlyiftheyhaveahis-toryofprevioustickbites.[Strengthofrecommendation:Moder-ate;CEvidence]SummaryStatement6:Avoidallmammalianmeatsinpatientswithalpha-galallergybecausethisoligosaccharideantigeniswidelyexpressedinmammaliantissues.[Strengthofrecommen-dation:Moderate;CEvidence]SummaryStatement7:Evaluatepatientswithlatexallergyforthepossibilityofcross-reactivitytobanana,avocado,kiwi,chest-nut,potato,greenpepper,andotherfruitsandnuts.Individualizedmanagementisrecommendedbecauseclinicalreactionscausedbythiscross-reactivitycanrangefrommildtosevere.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement8:AdvisepatientsnottobeconcernedaboutingestinggeneticallymodiÞedfoodsgiventhecurrentstateofknowledgeandtheUSFoodandDrugAdministrationÕsscreeningrequirementstoruleoutallergenicityofgeneticallymodiÞedfoods.[Strengthofrecommendation:Weak;DSummaryStatement9:ManagenonÐIgE-mediatedreactionstofoodswithappropriateavoidanceandpharmacotherapyasindi-catedwiththeunderstandingthatthespeciÞcroleofimmunity(eg,IgA,IgM,IgG,andIgGsubclasses)intheseformsoffoodal-lergyhasnotbeendemonstrated.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement10:Determinewhetherthereportedhis-toryoffoodallergy,whichoftenprovesinaccurate,andlaboratorydataaresufÞcienttodiagnosefoodallergyorwhetheranoralfoodchallenge(OFC)isnecessary.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement11:ConsiderthenaturalcourseofallergiestospeciÞcfoodswhendecidingonthefrequencyoffoodallergyfollow-upevaluations,recognizingthatallergiestocertainfoods(milk,egg,wheat,andsoy)generallyresolvemorequicklyinchildhoodthanothers(peanut,treenuts,Þsh,andshellÞsh).Theseobservationscouldsupportindividualizedfollow-up(ie,roughlyyearlyre-evaluationsoftheseallergiesinchildhood)withlessfrequentretestingifresultsremainparticularlyhigh(eg,�20-50/L).[Strengthofrecommendation:Moderate;CEvidence]SummaryStatement12:Encourageexclusivebreast-feedingfortheÞrst4to6monthsoflife.[Strengthofrecommendation:Weak;CEvidence]SummaryStatement13:Forinfantswithafamilyhistoryofatopy,considerapartiallyorextensivelyhydrolyzedinfantformulaforpossiblepreventionofatopicdermatitisandinfantcowÕsmilkallergyifexclusivebreast-feedingisnotpossible.[Strengthofrecommendation:Moderate;BEvidence]SummaryStatement14:DonotrecommendmaternalallergenavoidanceoravoidanceofspeciÞccomplementaryfoodsatwean-ingbecausetheseapproacheshavenotprovedeffectiveforprimarypreventionofatopicdisease.[Strengthofrecommenda-tion:Weak;CEvidence]SummaryStatement15:Donotroutinelyrecommendsupple-mentationofthematernalorinfantdietwithprobioticsorprebi-oticsasameanstopreventfoodallergybecausethereisinsufÞcientevidencetosupportabeneÞcialeffect.[Strengthofrecommendation:Weak;CEvidence]SummaryStatement16:Donotroutinelyrecommendthatpatientswithchronicidiopathicurticaria(CIU)avoidfoodscontainingadditives.[Strengthofrecommendation:Strong;BSummaryStatement17:Donotroutinelyinstructasthmaticpa-tientstoavoidsulÞtesorotherfoodadditivesunlesstheyhaveapriorreactiontosulÞtes.SulÞtesaretheonlyfoodadditiveprovedtotriggerasthma.Althoughthesereactionscanbesevere,evenlife-threateninginsensitivesubjects,theyarerare.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement18:Considernaturalfoodadditivesintheevaluationofpatientswithahistoryofunexplainedingestant-relatedanaphylaxis.[Strengthofrecommendation:Moderate;CSummaryStatement19:Patientswhoexperienceanadversere-actiontofoodadditivesshouldbeevaluatedforsensitivitytoannattoandcarmine.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement20:Cliniciansshouldbeawarethatavoid-ancemeasuresareappropriateforpatientswithhistoriescompat-iblewithadversereactionstoanadditiveuntildiagnosticevaluationcanbeperformed.[Strengthofrecommendation:Moderate;CEvidence]SummaryStatement21:Cliniciansshouldnotrecommendfoodadditiveavoidanceintheirpatientswithhyperactivity/attentiondeÞcitdisorder.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement22:Theclinicianshouldobtainadetailedmedicalhistoryandphysicalexaminationtoaidinthediagnosisoffoodallergy.[Strengthofrecommendation:Strong;DSummaryStatement23:TheclinicianshouldusespeciÞcIgEtests(skinpricktests,serumtests,orboth)tofoodsasdiagnostictools;however,testingshouldbefocusedonfoodssuspectedofprovokingthereaction,andtestresultsaloneshouldnotbeconsidereddiagnosticoffoodallergy.[Strengthofrecommenda-tion:Strong;BEvidence]SummaryStatement24:Component-resolveddiagnostictestingtofoodallergenscanbeconsidered,asinthecaseofpea-nutsensitivity,butitisnotroutinelyrecommendedevenwithpea-nutsensitivitybecausetheclinicalutilityofcomponenttestinghasnotbeenfullyelucidated.[Strengthofrecommendation:Weak;CEvidence]SummaryStatement25:TheclinicianshouldconsiderOFCstoaidinthediagnosisofIgE-mediatedfoodallergy.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement26:Ifclinicalhistoryisnotconsistentwithanaphylaxis,performagradedOFCtoruleoutfoodallergy.OpenJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL foodchallengeisbothcost-andtime-efÞcient.[Strengthofrecommendation:Moderate;CEvidence]SummaryStatement27:Ifthediagnosisisstillunclearafteropenfoodchallenge,thenrecommendablindfoodchallenge.[Strengthofrecommendation:Moderate;BEvidence]SummaryStatement28:EliminationdietsanddietdiariescanbeusedasanadjunctivemeanstodiagnosefoodallergiesbutarenottobedependedonsolelyforconÞrmingadiagnosis.[Strengthofrecommendation:Weak;DEvidence]SummaryStatement29:Adiagnosisoffood-dependent,exercise-inducedanaphylaxisshouldbeconsideredwheninges-tionofcausalfoodorfoodsandtemporallyrelatedexerciseresultinsymptomsofanaphylaxis.Theclinicianshouldrecognizethatsymptomsonlyoccurwithingestionofthecausalfoodorfoodsproximatetoexerciseandthatingestionofthefoodintheabsenceofexercisewillnotresultinanaphylaxis.[Strengthofrecommen-dation:Strong;BEvidence]SummaryStatement30:Theclinicianshouldconsiderthediag-nosisoforalallergysyndrome(pollen-foodallergy)andobtainspeciÞcIgEtestingtopollensinpatientswhoexperiencelimitedoropharyngealsymptomsafteringestionoffoodantigensthatcross-reactwithpollenantigens.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement31:AdiagnosisofIgE-mediatedcontacturticariashouldbeconsideredinpatientswithahistoryofimme-diateurticarialrashatthesiteofcontactwithafoodallergen.[Strengthofrecommendation:Weak;DEvidence]SummaryStatement32:DonotroutinelyobtaintotalserumIgElevelsforthediagnosisoffoodallergy.[Strengthofrecommenda-tion:Strong;CEvidence]SummaryStatement33:Donotperformintracutaneoustestingforthediagnosisoffoodallergy(seediscussion).[Strengthofrecommendation:Strong;BEvidence]SummaryStatement34:Unprovedtests,includingallergen-speciÞcIgGmeasurement,cytotoxicityassays,appliedkinesi-ology,provocationneutralization,andhairanalysis,shouldnotbeusedfortheevaluationoffoodallergy.[Strengthofrecommen-dation:Strong;CEvidence]SummaryStatement35:Althoughroutineuseofatopypatchtestsfordiagnosisoffoodallergyisnotrecommended,theuseoffoodatopypatchtestsinpatientswithpediatriceosinophilicesophagitis(EoE)havebeendemonstratedtobevaluableinas-sessingpotentialfoodtriggers.[Strengthofrecommendation:Moderate;CEvidence]SummaryStatement36:ThephysicianshouldusethepatientÕsmedicalhistory,responsetoatrialofeliminationofthesuspectedfood,andOFCtoestablishadiagnosisoffoodproteinÐinducedenterocolitissyndrome(FPIES).However,whenthehistoryindi-catesthatinfantsorchildrenhaveexperiencedhypotensiveepi-sodesormultiplereactionstothesamefood,adiagnosiscanbebasedonaconvincinghistoryandabsenceofsymptomswhenthecausativefoodiseliminatedfromthediet.[Strengthofrecom-mendation:Strong;BEvidence]SummaryStatement37:TheclinicianshouldbeawarethatagastrointestinalevaluationwithendoscopyandbiopsyisusuallynotrequiredforthediagnosisofFPIESandallergicproctocolitiswithsymptomsthatrespondtoeliminationoftheoffendingfoodandrecurwhenthefoodisreintroducedintothediet.[Strengthofrecommendation:Weak;CEvidence]SummaryStatement38:Measurementoffood-speciÞcIgGandantibodiesinserumarenotrecommendedforthediagnosisofnonÐIgE-mediatedfood-relatedallergicdisorders.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement39:Atrialoftwicedailyproteinpumpin-hibitor(PPI)therapyfor8weeksbeforediagnostictestingforEoEisrecommendedtoexcludegastroesophagealreßuxdisease(GERD)andPPI-responsiveesophagealinÞltrationofeosino-phils.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement40:ThediagnosisofEoEshouldbebasedonthepresenceofcharacteristicsymptomsandendoscopicfea-turesandthepresenceof15ormoreeosinophilsperhigh-powerÞeldquantiÞedbyapathologistusinghematoxylinandeosinstainingofesophagealbiopsyspecimensat400lightmi-croscopy.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement41:Eosinophilicgastroenteritis(EGE)shouldbeconsideredaconstellationofclinicalsymptomsincom-binationwithgastric,smallintestine,and/orlargeintestineinÞl-trationofeosinophilsatgreaterthanthereportednormalnumbersofgastricandintestinaleosinophils.[Strengthofrecom-mendation:Weak;DEvidence]SummaryStatement42:Prescribeatargetedallergenelimina-tiondietasthetreatmentforknownorstronglysuspectedfoodal-lergy.Educationaboutproperfoodpreparationandtherisksofoccultexposureisessential.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement43:Recommendconsultationwithanutri-tionistforgrowingchildreninwhomeliminationdietsmightaffectgrowth,aswellasthosepatientswithmultiplefoodal-lergies,poorgrowthparameters,orboth.Cliniciansmustbeawareofthenutritionalconsequencesofeliminationdietsandcertainmedications,suchasesomeprazole,especiallyingrowingchildren.SpeciÞcally,identifyingalternativedietarysourcesofcalciumandvitaminDiscriticalforpatientswithmilkallergy.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement44:ReviewrecognitionandtreatmentofIgE-mediatedfood-relatedallergicreactionswitheachpatientandcaregivers,asappropriate.Emphasisshouldbeplacedonpromptawarenessofanaphylaxisandswiftintervention.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement45:Discussself-caremanagementtech-niques,especiallywithhigh-riskpatients,(eg,adolescents,youngadults,andasthmaticpatients),focusingonriskreductionandrecognitionandtreatmentofanaphylaxis.[Strengthofrecom-mendation:Strong;CEvidence]SummaryStatement46:UseepinephrineasÞrst-linemanage-mentforthetreatmentofanaphylaxis.[Strengthofrecommenda-tion:Strong;CEvidence]SummaryStatement47:Ensurethatself-injectableepinephrineisreadilyavailabletothepatientandinstructthepatient,care-giver,orbothontheimportanceofitsuseandself-administration,asrelevant.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement48:Evaluatechildrenwithfoodal-lergiesatregularintervals(1-2years),accordingtothepa-tientÕsageandthefoodallergen,todeterminewhetherheorsheisstillallergic.Iffoodallergyisunlikelytochangeovertime,asinadults,periodicre-evaluation(2-5years)isrecommended,dependingonthefoodallergy.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement49:Forpatientswithfood-dependent,exercise-inducedanaphylaxis,avoidfoodingestionwithin2to4hoursofexerciseforpreventionofsymptoms,andprovideJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL prompttreatmentwithonsetofsymptoms.[Strengthofrecom-mendation:Strong;CEvidence]SummaryStatement50:Managepollen-foodallergysyndromeororalallergysyndromebydietaryavoidanceofrawfruits,veg-etables,orbothbasedonthepatientÕssymptomproÞleseverity.Theextentoffoodavoidancedependsontheseverityoforopha-ryngealsymptoms.[Strengthofrecommendation:Strong;CSummaryStatement51:Theclinicianshouldunderstandthevariousclinicalpresentationsoftheseconditions(ie,FPIES/proctocolitis/enteropathy),educatepatientsandcareprovidersaboutcommonfoodtriggers,andrecommendstrictfoodavoid-anceofallergenicfoodsforsymptommanagement.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement52:UsevolumereplacementtherapyfortheacutecaremanagementofpatientswithFPIES.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement53:SeepatientswithFPIESandallergicgastrointestinaldisordersatregularintervalsandconsiderrechal-lengeinanappropriatemedicalfacilitybasedonthenaturalhis-toryofthespeciÞcdisorder.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement54:ConsiderserialtissuebiopsiesaspartofdiseasemanagementinpatientswithEoE.SymptomsaloneorendoscopywithoutbiopsycannotbeusedasanaccurategaugeofEoEdiseaseactivity.[Strengthofrecommendation:Strong;CSummaryStatement55:ConsiderassessmentforaeroallergensensitizationbecauseEoEcanbetriggeredbyaeroallergensinhu-mansubjectsandanimalmodelsandtheremightbeaseasonalitytoEoEdiagnoses.[Strengthofrecommendation:Moderate;DSummaryStatement56:ConsiderfoodallergyevaluationwithbothskinprickandpatchtestingforEoEtoruleoutpossiblefoodtriggers.RememberthatpositiveserumspeciÞcIgElevels,foodskinpricktestresponses,andfoodpatchtestresultsarenotsufÞ-cienttodiagnosefoodtriggersforEoE.[Strengthofrecommen-dation:Moderate;CEvidence]SummaryStatement57:Considertheuseoftargetedorempiricfood-eliminationdietsoraminoacidÐbaseddietsforsuccessfulEoEtherapy.[Strengthofrecommendation:Strong;BEvidence]SummaryStatement58:ConsidertheuseofswallowedtopicalesophagealcorticosteroidsforsuccessfulEoEtherapy.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement59:Referraltoagastroenterologistforesophagealdilationisrecommendedforhigh-gradestenosisbutdoesnotprovideinßammatorycontrol.[Strengthofrecommen-dation:Moderate;CEvidence]SummaryStatement60:AdministeroralcorticosteroidsforEGEasthepreferredtherapy.[Strengthofrecommendation:Weak;CEvidence]SummaryStatement61:Althoughimmunotherapeuticap-proaches,suchasoralimmunotherapy,inclinicaltrialsshowpromiseintreatingfoodallergy,theyarenotreadyforimplemen-tationinclinicalpracticeatthepresenttimebecauseofinade-quateevidencefortherapeuticbeneÞtoverrisksoftherapy.[Strengthofrecommendation:Strong;AEvidence]SummaryStatement62:Developawrittenactionplanfortreat-mentofallergicreactionstofoodforadultsandchildren.[Strengthofrecommendation:Moderate;DEvidence]SummaryStatement63:Inquireaboutandaddressbehavioralchangesbecauseofbullyinginpatientswithfoodallergy.Thisin-quiryshouldincludeadultsandchildren.[Strengthofrecommen-dation:Strong;DEvidence]SummaryStatement64:Teachpatientsthatingestion,ratherthancasualexposurethroughtheskinorcloseproximitytoanallergen,isalmosttheonlyroutefortriggeringsevereallergic/anaphylacticreactions.[Strengthofrecommendation:Strong;CPREFACEAsdeÞnedbytheNationalInstituteofAllergyandInfectiousDiseases(NIAID)expertpanel,foodallergyisdeÞnedhereÔÔasanadversehealtheffectarisingfromaspeciÞcimmuneresponsethatoccursreproduciblyonexposuretoagivenfood.ÕÕHere,thetermallergyisnotlimitedtoIgE-mediatedimmunologicreactionsandisusedtoconnotetheinductionofclinicalsignsandsymptoms,asopposedto,whichin-dicatesthepresenceofIgEantibodiestoafood,oftenintheabsenceofclinicalsymptomatology.AlthoughtheprevalenceoffoodallergyoverallandofallergytospeciÞcfoodsisuncer-tainbecausestudiesvaryinmethodologicalapproaches,aller-gistswhohavebeeninpracticeforatleastadecadehavebeenconfrontedwithanever-growingnumberofpatientswithfoodallergy.Onthebasisofarecentextensivereviewofthelitera-ture,foodallergyisestimatedtoaffectmorethan1%to2%andlessthan10%ofthepopulation.Therearelimiteddatatosug-gestthatfoodallergyprevalencehasincreased,butnationalsur-veyssuggestthatpeanutallergyhastripledsincethelateInconsideringanumberofpublishedstudies,isapparentthatestimatesoffoodallergyprevalencearehighestwhenbasedonself-report(approximately12%to13%)comparedwithestimatesbasedonstudiesusingtests,suchasoralfoodchallenges(OFCs;approximately3%).Thisobserva-tionregardingadiscordanceofsuspectedandprovedfoodal-lergyunderscorestheimportanceofusingproveddiagnosticmethodstoevaluateindividualpatientssuspectedofahavingfoodallergy.Thephysicianshouldapplyinformationregardingepidemio-logicfeaturesoffoodallergywhenapproachingdiagnosisandmanagement,recognizingthatself-reportedfoodallergyismorecommonthanprovedfoodallergy,thatfoodallergyismorecommoninchildren,thatalimitednumberoffoodsaccountformostsigniÞcantfoodallergies,andthatfoodallergyoccursmorecommonlyinpersonswithotheratopicdiseases.Thereareanumberofepidemiologicfeaturesregardingfoodallergythatmightbehelpfulinconstructingaprioriassessmentofriskandconsiderationofpotentialtriggerswhenevaluatingindividualpa-tients.Althoughmorethan170foodshavebeenidentiÞedastrig-gersoffoodallergy,thosecausingmostofthesigniÞcantallergicreactionsincludepeanut,treenuts,Þsh,shellÞsh,milk,egg,wheat,soy,andseeds.Foodallergy(tofoodsotherthanshellÞshandfruits/vegetables)ismorecommoninchildrenthaninadults.Asdescribedelsewhereinthisparameter,milk,egg,wheat,andsoyallergiesaremorecommoninchildrenthaninadults.Thereisahighco-occurrenceoffoodallergywithotheratopicdiseases,includingatopicdermatitis,asthma,andallergicInparticular,childrenwithmoderate-to-severeatopicdermatitisappeartohaveasigniÞcantrisk(approximatelyJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL 35%)offoodallergy.Therearenosimilarstudiesinadults,andthereforetheprevalenceofco-occurringfoodallergyinadultswithatopicdermatitisisunknown.CutaneousreactionstofoodsaresomeofthemostcommonpresentationsoffoodallergyandincludeIgE-mediated(urticaria,angioedema,ßushing,andpruritus),cell-mediated(contactdermatitisanddermatitisherpetiformis),andmixedIgE-andcell-mediated(atopicdermatitis)reactions.ThesearedeÞnedasfollows:AcuteurticariaisacommonmanifestationofIgE-mediatedfoodallergy,althoughfoodallergyisnotthemostcommoncauseofacuteurticariaandisrarelyacauseofchronicur-Urticariaisthemostcommonsymptominpatientsexperiencingfood-inducedanaphylaxis.Angioedemamostoftenoccursincombinationwithurti-cariaand,iffoodinduced,istypicallyIgEmediated.gioedemaisalsoacommonsymptominpatientswithAtopicdermatitis/atopiceczemaislinkedtoacomplexinteractionbetweenskinbarrierdysfunctionandenviron-mentalfactors,suchasirritants,microbes,andaller-InsomesensitizedpatientsfoodallergensmightbesigniÞcanttriggersforatopicdermatitis/atopiceczema,especiallyininfantsandyoungchildren,inwhomfoodal-lergensareestimatedtobeasigniÞcanttriggerin30%to40%ofpatients.Allergiccontactdermatitisisaformofeczemacausedbycell-mediatedallergicreactionstochemicalhaptenspresentinsomefoods,eithernaturally(eg,mango)orasaddi-tives.Clinicalfeaturesincludemarkedpruritus,erythema,papules,vesicles,andedema.ContacturticariacausedbyfoodallergyisanIgE-mediatedreactioncausedbydirectskincontactinasensitizedsub-jects.Althoughcommon,reactionsaretypicallynotsevereandconÞnedonlytothesiteofcontact.Gastrointestinalreactionsarealsoafrequentmanifestationoffoodallergy.However,thefrequencyandunpredictabilityofanaphylaxiscausethemostanxietyinpatientsandtheirfamilies.Theincidenceoffood-inducedanaphylaxisisunclear.The5USstudiesthathavebeenconductedtoestimatetheprevalenceoffood-inducedanaphylaxishavefoundwidedifferencesintheratesofhospitalizationoremergencydepartmentvisitsforanaphylaxis,asassessedbyInternationalClassiÞcationofDiseasescodesormedicalrecordreview,from1/100,000popu-lationtoashighas70/100,000population.Theproportionofanaphylaxiscasesthoughttobeduetofoodsinthesestudiesalsovariedwidely,rangingfrom13%to65%,withthelowestpercent-agesfoundinthosestudieswithmorestringentdiagnosticcriteriaforanaphylaxis.Onestudyreportedthatthenumberofhospital-izationsforanaphylaxisincreasedwithincreasingage,whereasanotherstudyreportedtotalcasesofanaphylaxiswerealmosttwiceashighinchildrenasinadults.Thesevariationsmightbeduetodifferencesinstudymethodsordifferencesinpopulationsstudied.Althoughitisestimatedthatgreaterthan12millionAmericanshavefoodallergies,datafromtheUSFoodandDrugAdministrationÕsNationalElectronicInjurySurveillanceSystemofemergencydepartmentencounterssuggestabout125,000visitsperyearforfood-inducedallergicreactions,14,000visitsperyearforfood-inducedanaphylaxis,andapprox-imately3,100hospitalizationsperyearrelatedtofoodallergy.Fatalitiesarerareandestimatedtobelessthan100peryear,withthemajorityoccurringduringthesecondthroughfourthde-cadesoflife.SECTIONI:CLASSIFICATIONOFMAJORFOODALLERGENS,CROSS-REACTIVITIES,GENETICALLYMODIFIEDFOODS,ANDCLINICALIMPLICATIONSClassiÞcationSummaryStatement1:Evaluatethepatientforpossiblefoodal-lergywiththeunderstandingthatarelativelysmallnumberofal-lergenscauseahighproportionoffoodallergy(eg,cowÕsmilk,henÕsegg,soy,wheat,peanut,treenuts,Þsh,andshellÞsh).SeeSummaryStatement48formanagement.[Strengthofrecommen-dation:Strong;BEvidence]ItisgenerallybelievedthatvirtuallyanyfoodcanelicitanIgE-mediatedallergicreactioninapredisposedsubject,andmorethan170foodshavebeenreportedtobeallergenic.However,itisnowwellrecognized,basedonmanystudies,thatallergytocertainfoodsappearstobeespeciallycommon.Inorderofprevalence,thesemostcommonfoodallergensaremilk,egg,peanut,treenuts,crustaceanshellÞsh,Þsh,wheat,andsoy.ThisisconsistentwiththeÞndingthatallergensbelongtoaveryrestrictednumberofproteinfamilies.ItisimportanttonotethatprevalencedataaremostoftenderivedfromstudiesofwesternizedpopulationsthatfocusonarelativelylimitednumberoffoodsandthattruefoodallergyprevalenceisdifÞculttoaccuratelyascertainbecauseofalackoflargerigorouslyperformedstudies.Inaddition,differingpatternsofconsumptionandallergicsensitizationmightinßuencetherelevanceofspeciÞcfoodstothepublichealthofdifferentcountries.Forexample,studiesofEuropeanpatientshaveidentiÞed,inadditiontothecommonallergensnamedabove,celery,mustard,sesame,lupine,stonefruits,andmolluscanshellÞshasprevalentallergens.Foodallergensbelongtoalimitednumberofproteinfamiliesthoughttobeallergenicinpartbecauseofsharedphysicochem-icalcharacteristics.Allergenicproteinsareincreasinglybeinganalyzedwithdetailedmolecular,biochemical,andcomputationaltechniquesandthenclassiÞed,organized,andcataloguedintopublicdatabasesthatarenowavailabletoscientistsandpractitioners;examplesincludeallergenonline.orgallergen.orgallergome.orgimmuneepitope.org,andfermi.utmb.edu/SDAP/.Inaddition,theimmuneresponsestotheseallergensarebeinganalyzedwithmo-lecularandimmunologictechniquestolinkclinicaloutcomestospeciÞcantibody-bindingpatterns.ThesescientiÞcandtechnicaladvancesarecontributingtoanewunderstandingofthetaxon-omyofallallergens,includingfoodallergens.Onekeyfeatureofthisnewunderstandingisthehighlyrestricteddistributionofallergens(2%to5%ofallknownstructuralproteinfamilies),regardlessoftheirsourceandrouteofexposure.Thissug-geststhatcertainpropertiesofproteinscanconferallergenicity,althoughthisremainscontroversial.Inparticular,aputativefoodallergenmusthavephysicochem-icalcharacteristicsthatwillpermitittosurvivetheharshdigestiveprocessandelicitanimmunologicresponseonexposuretothemucosalimmunesystemofanatopicsubject.Suchcharacteristicsarethoughttoincludewatersolubility,glycosylationresidues,relativelylowmolecularweight,resistancetodigestionbyheatandproteases,andabundancewithinthefoodsource.plantandanimalfoodallergensbelongtoalimitednumberofJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL majorproteinfamiliespossessingthesecharacteristics,andtheycanbesigniÞcantlyaffectedbyfoodprocessing.Abriefsum-maryofthemajorfamiliesfollows.Toobtainanup-to-dateclas-siÞcationoffoodallergens,theirproteinfamilyrelationships,andÔÔfactsheetsÕÕsummarizingkeypoints,pleasevisithttp://www.meduniwien.ac.at/allergens/allfam/search.phpFoodallergensofanimaloriginbyfamily:Tropomyosins:Theinvertebratetropomyosinsareafamilyofmuscleproteinssharinghomologyacrossspecies(butnotwithvertebratetropomyosins),andthereforetheyactaspanallergens.Thesearethemajorallergensincrusta-ceansandmollusksandaregenerallyheatstableandcross-reactive.Parvalbumins/EF-handproteins:ThesemuscleproteinsaremajorallergensfromvertebrateÞshandfrogsandpossessacalcium-bindingdomainreferredtoasanEF-handmotif.Theallergensinthissecond-largestfamilyareconsideredtobehighlycross-reactivepanallergens.:Caseinsbindcalciuminmammalianmilkandsta-bilizeitinmicellarform.ThesearethemajorallergensincowÕsmilk,andbecauseofhighsequencehomology�_90%),theyarecross-reactivewithothermammalianmilksfrequentlyconsumedbyhumansubjects(eg,goatÕsandsheepÕsmilk).Otheranimalmilksfromhorses,donkeys,camels,andhumansubjectshavecaseinswithroughly60%homology,possiblyaccountingforlessallergenicity.Minorfamilies:Theseincludelipocalins,lysozymes,trans-ferrins,serpins,oligosaccharides,andovomucoids/KazalFoodallergensofplantoriginbyfamily:Prolaminsuperfamily:Theprolaminsuperfamilycontainsthehighestnumberofplantfoodallergensandischarac-terizedbyrichdisulÞdebondsandacoreof8conservedcysteineresidues,providingstabilityandresistancetoThissuperfamilycontainsthe2Salbuminseedstorageproteinsofseeds,treenuts,andlegumes,includingpeanut;nonspeciÞclipidtransferproteinsfromfruits,nuts,seeds,vegetables,pollen,andlatex;andthe-amylase/trypsininhibitorsfoundinwheat,barley,rye,corn,andrice.Cupinsuperfamily:Thecupinsarealargeandfunctionallydiversesuperfamilyofproteinsthatsharea-barrelstruc-turalcoredomain.Cupinallergensareseedstorageglobu-linsrepresentingmajorfoodallergensfromlegumes,nuts,andseeds.Seedstorageglobulinscanbegroupedinto2families:vicilinsandlegumins.Betv1superfamily:ThemajorbirchpollenallergenBetv1isamemberofthepathogenesis-relatedprotein10fam-ilywithinthissuperfamily.ManypatientssensitizedtoBetv1alsohaveoralallergysyndrome(OAS)afteringestionofcertainfruitsandvegetables,whichiscausedbyIgEcross-reactivitybetweenBetv1andhomologousallergensfromplantfoods.MostBetv1Ðrelatedfoodallergenswerefoundinmembersofcertainplantfamilies:Rosaceae(apple,pear,andstonefruits),Apiaceae(celeryandcarrot),andFabaceae(soybeanandpeanut).Minorfamilies:TheseincludeclassIchitinases,proÞlins,proteaseinhibitors,lectins,andthaumatin-likeproteins.Cross-reactivityCross-reactivityisanimmune-mediatedphenomenonthatcanoccurwhenaspeciÞcantibodyreactsnotonlytotheoriginalallergenbutalsotoadifferenthomologousallergen.WhenafoodallergensharessufÞcientstructuralorsequencesimilaritywithadifferentfoodallergenoraeroallergen,epitopesonthesecondallergenareboundbycross-reactiveantibodies,triggeringanadversereactionsimilartothatelicitedbytheoriginalfoodallergen(TableE1Immunologically,thisisdistinctfromcoal-lergy,inwhichpatternsofreactivitytomultiplefoodsmightbeprevalentbutarenotmediatedbysharedepitope-speciÞcanti-bodies.Accurateepidemiologicdataontheprevalenceofclinicalcross-reactivitiesaregenerallylimitedbythelackoflarge,controlledpopulation-basedstudiesincorporatingOFCs.Despitehavinghighsequencehomologyinsomecases,theabilityofcross-reactiveallergenstomediateclinicalallergicreactionsishighlyvariableandoftendependsonthespeciÞcfoodsinvolved.Inapatientclinicallyallergictoalegume,itiscommontodetectIgEtootherlegumes,giventhehighhomologysharedbythisfamilyofplants.Despitethisobservation,clinicalcross-reactivitytootherlegumesisgenerallyuncommon,althoughthismightbearegionalobservationinßuencedbypollenexposureandtheprominenceoflegumesinthediet.Forexample,recentstudiesfocusedprimarilyonpopulationsinMediterraneanEuropehavedemonstratedclinicalallergiestomultiplelegumes,particularlyinpatientsallergictolupine,lentil,andPatientswithpeanutallergy.Becausepatientswithpeanutallergygenerallytolerateotherlegumes,includingsoy,arecommendationtoempiricallyavoidalllegumesisgenerallyunnecessary.Possiblelegumeallergyshouldbeevaluatedonacase-by-casebasisinpatientswithpeanutallergy.Patientswithsoyallergy.Theabilitytoevaluatecross-reactivityinpatientsallergictosoyhasbeenhamperedbyalackofunderstandingofthemajorsoyallergens,althoughprogressisbeingmadeinthisarea.Althoughcross-reactivitybetweensoybeanandotherlegumesisextensiveinvitrobecauseofthehighhomologybetweenproteins,clinicalcross-reactivityofpa-tientswithsoyallergytootherlegumesisgenerallyuncommon,andextensiveeliminationdietsbasedonlyonpositivetestresultsarenotrecommended.PatientswithIgE-mediatedwheatallergyaloneshowextensiveinvitrocross-reactivitytoothercerealgrainsandgrasspollens.However,clinicalcross-reactivitytomultiplecerealgrainsoccursinaminorityofpatientssensitizedtomultipleThereforeeliminationofallgrains(eg,wheat,rye,barley,oats,rice,andcorn)fromthedietofapatientwithgrainallergyisnotrecommendedandmightbenutritionallyharmful.Fruitsandvegetables.Self-reportofimmediatereactionsandsensitizationtomultiplefruitsandvegetablesarecommon,butveryfewstudieshavebeenperformedthatincorporaterigorousmethods,includingfoodchallenges.ThusitisuncleartowhatextentsuchreportsreßectnonspeciÞcfactors(eg,contactorirritantdermatitis),OAS,ortruegastrointestinalfoodallergencross-reactivity.Althoughthereareexceptions(eg,lipidtransferproteinsactingaspanallergensinMediterraneanpatients),itisuncommonforcross-reactivityamongandbetweenfruitsandvegetablestoresultinseverereactions,andextensiveeliminationdietsarenotrecommended.JALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL SummaryStatement2:AdvisepatientswhoareallergictocertainspeciÞcfoodsabouttheriskofingestionofsimilarcross-reactingfoods.Examplesincludeingestionofothertreenutsinpatientswithtreenutallergy(eg,walnutandpecanorpis-tachioandcashew),Crustaceainpatientswithcrustaceanseafoodallergy,vertebrateÞshinpatientswithÞshallergy,andothermammalianmilksinpatientswithcowÕsmilkallergy.[Strengthofrecommendation:Strong;CEvidence]Treenuts.Cross-reactivityandcoallergyamongtreenutsisandserologicstudiesdemonstrateIgEbindingtomultipletreenuts.Inparticular,strongcorrelationsbetweenIgElevelstocashewandpistachio,aswellasbetweenwalnutandpecan,havebeenobservedandconÞrmedwithinhibitionELISAexperiments.Thesestudiessuggestsharedallergensexistamongtreenutsandbetweentreenutsandotherplant-derivedfoodsandpollen.Reactionstothesesharedallergenscanbeseriousandcanoccuroninitialexposure.Carefulassess-mentisnecessarybeforeconsideringwhethertointroduceothernutsintothediet.Thisassessmentmightinvolvetheuseofsuper-visedOFCstomultiplenutsbecauseskinpricktest(SPT)resultsmightnotbereliableindeterminingwhichnutscanbePeanutandtreenuts.Between25%and50%ofpatientswithpeanutallergyarecoallergictotreenuts,andthereissigniÞcantcross-reactivitybetweenhomologousT-andB-cellepitopeswithinpeanutallergensandcertaintreenuts(eg,almond,walnut,pecan,hazelnut,andBrazilnut).mentofpatientswithpeanutallergyseekingguidanceontreenutingestionshouldbeindividualized,butbecauseofprac-ticalconcernsaboutcross-contaminationandthedifÞcultyinreliablyidentifyingspeciÞctreenuts,avoidanceofalltreenutsbyyoungchildrenwithpeanutallergyshouldbeTheclinicianshouldbeawareofseveralimportantprinciplesrelatedtocross-reactivitythatinßuencethecareofpatientsallergictocrustaceanshellÞsh.First,invertebratetropo-myosinactsasamajorpanallergen,invitroreactivitybetweenCrustaceaandarthropods(eg,housedustmiteandcockroach,whichalsoexpressinvertebratetropomyosin),aswellasconsiderableriskofclinicalcross-reactivitybetweenCross-reactivitycanresultinseverereactions,andavoidanceofallmembersofthecrustaceanfamilyisgener-allyrecommended;lesswelldeÞnediscross-reactivitybetweenmollusksandcrustaceans.Second,tropomyosinsdonotcross-reactwiththoseinvertebrateÞsh(parvalbumins),andavoidanceofbothvertebrateÞshandcrustaceansisgenerallyunnecessaryonthebasisofcross-reactivity.VertebrateÞsh.IgEcross-reactivityafterinvitroorskinpricktestingiscommonbetweendifferentspeciesofvertebrateÞshbecauseofthesharedexpressionofparvalbuminsacrossspe-Theclinicalrelevanceofthiscross-reactivityvarieswidely.Carefulindividualizedevaluation,includingtheuseofOFCs,asindicated,mightbenecessarytodetermineclinicaltolerancetovariousvertebrateÞsh.Whenevaluatingandtreatingpatientsforpotentialallergytomultiplerelatedfoods,coallergy,cross-contamination,orbothmightneedtobeconsidered.SummaryStatement3:Avoidothermammalianmilks,suchasgoatÕsmilkorsheepÕsmilk,inpatientswithcowÕsmilkallergybecauseofhighlycross-reactiveallergens.[Strengthofrecom-mendation:Strong;BEvidence]Becauseofhighhomologybetweenproteinsinmilkfromcows,goats,andsheep,patientswithmilkallergyshouldavoidallofthem.Milkfrommaresorcamelsmightbelesscross-reactive.Generallyspeaking,plant-basedalternativesareSummaryStatement4:Advisepatientswithseafoodallergythattheyarenotatincreasedriskofareactiontoradiocontrastmedia.ThereisnodocumentedrelationshipbetweennonÐIgE-mediatedanaphylacticreactionstoradiocontrastmediaandallergytoÞsh,crustaceanshellÞsh,oriodine.[Strengthofrecom-mendation:Strong;DEvidence]Systemic,nonÐIgE-mediatedimmediatehypersensitivityre-actionsoccurin1%to3%ofpatientsreceivingionicradio-contrastmediaandinlessthan0.5%ofthosereceivingnonionicagents.EstablishedriskfactorsincludepriornonÐIgE-mediatedanaphylacticreactionsfromcontrastinfusion,femalesex,blockerexposure,andasthma.Theevidenceimplicatingatopy(includingallergytofoodsordrugs)asariskfactorisweak,andforthisreason,riskreductionmeasuresarenotrequiredintheabsenceoftheotherfactorslistedabove.Althoughseafoodcancontainiodine,theallergenicityofthesefoodsisrelatedtospe-ciÞcmuscleproteins(tropomyosinandparvalbumin,asprevi-ouslydescribed)thatdonotcontainiodine.ThereforeallergytoÞshorshellÞshdoesnotindicateanallergyorsensitivitytoThereisnoconvincingevidencethattheinorganiciodinelevelspresentinseafoodorintopicallyappliediodine-containingsolutionsarerelatedtoadverseeventsfromcontrastmediaorthatpatientswithseafoodallergyareatparticularlyincreasedriskforsystemicreactionstocontrastmedia.InVersion8oftheirManualonContrastMedia,newlyrevisedin2012,theAmericanCollegeofRadiologyCommitteeonDrugsandContrastMediaissuedthefollowingstatement:ÔÔThepredic-tivevalueofspeciÞcallergies,suchasthosetoshellÞshordairyproducts,previouslythoughttobehelpful,isnowrecognizedtobeunreliable.AsigniÞcantnumberofhealthcareproviderscontinuetoinquirespeciÞcallyintoapatientÕshistoryofÔallergyÕtoseafood,especiallyshellÞsh.ThereisnoevidencetosupportthecontinuationofthispracticeÕÕ(AmericanCollegeofRadi-ology.ManualonContrastMedia,v8.http://www.acr.org/.AccessedOctober5,2012).SummaryStatement5:TestforIgEantibodiesspeciÞcfortheimmunogenicoligosaccharidealpha-galinpatientswhoreportadelayedsystemicreactiontoredmeatorunexplainedanaphy-laxis,particularlyiftheyhaveahistoryofprevioustickbites.[Strengthofrecommendation:Moderate;CEvidence]SummaryStatement6:Avoidallmammalianmeatsinpatientswithalpha-galallergybecausethisoligosaccharideantigeniswidelyexpressedinmammaliantissues.[Strengthofrecommen-dation:Moderate;CEvidence]Recently,delayedallergytomammalianmeatshasbeenlinkedtotheproductionofIgEtoalpha-galinsusceptiblesubjects,vastmajorityofwhomreporttickbites.Urticaria,angioe-dema,andanaphylaxiscanoccur3to6hoursaftereatingbeef,pork,lamb,andvenison,andthemechanismsforthisdelayremainpoorlyunderstood.Resultsofepicutaneoustestingtotheabovefoodsmightnotbestronglypositive,butinvitroforalpha-galIgEarenowcommerciallyavailable.Alpha-galÐspeciÞcIgE(sIgE)willrecognizeepitopespresentinalloftheseanimals,andthusallofthesemeatsshouldbeeliminatedfromtheJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL SummaryStatement7:Evaluatepatientswithlatexallergyforthepossibilityofcross-reactivitytobanana,avocado,kiwi,chest-nut,potato,greenpepper,andotherfruitsandnuts.Individualizedmanagementisrecommendedbecauseclinicalreactionscausedbythiscross-reactivitycanrangefrommildtosevere.[Strengthofrecommendation:Strong;CEvidence]ProteinsinproductsderivedfromthenaturalrubberlatextreeHeveabrasiliensissharehomologousepitopeswithmanyotherplantfoods.Approximately30%to50%ofpatientsallergictolatexmightbeclinicallyreactiveto1ormorefoods,typicallyfreshfruitsandnuts.Althoughirrelevantsensitizationismorecommonthantrueclinicalcross-reactivity,reactionstofruitinpa-tientswithlatexallergycanbesevere.Cautioniswarrantedwhenevaluatingsuchpatients.GeneticallymodiÞedorganismsinfoodsandthepotentialforallergenicitySummaryStatement8:AdvisepatientsnottobeconcernedaboutingestinggeneticallymodiÞedfoodsgiventhecurrentstateofknowledgeandtheUSFoodandDrugAdministrationÕsscreeningrequirementstoruleoutallergenicityofgeneticallymodiÞedfoods.[Strengthofrecommendation:Weak;DAlthoughthedeterminantsofallergenicityarethesubjectofcontinuedstudy,nosingleÞndingcanpredictwhetheragivenfoodproteinwillcauseallergyinhumansubjects.ThereforetheCodexAlimentariusCommissionoftheWorldHealthOrganiza-tionhasrecommendedaweight-of-evidenceapproachforallergenicityassessmentofthenovelfoodproteinsproducedthroughmolecularbiologictechniques.TheseassessmentsarelargelybasedonthecurrentknowledgeoffoodallergensandwhetherthegeneticallymodiÞedfoodinquestionmightactasorcross-reacttoaknownallergen.Todeterminewhetherthismightbethecase,thecodexrecommendsinvestigatingthehis-toryofhumanexposureandsafetyofthegeneproductorproductsandthenanalyzingandcomparingtheproteinsequenceandphys-icochemicalpropertieswiththoseofknownallergensbyusingcurrentbioinformaticstools.Whenthesepreliminaryassessmentssuggestrisk(�_35%sharedidentityover�_80aminoacidspan),sIgE-bindingstudieswithwell-characterizedserumfrompatientsallergictotheidentiÞedsourceorskinpricktestingwithrelevantsubjectsarealsoconducted.Perhapsinpartbecauseofthesafetyandallergenicityassessmentsperformedduringproductdevelopment,thereisnopublishedevidencetodateofallergicreactionstoanygeneticallymodiÞedproteinoranyadversehumanhealthreactionsassoci-atedwithconsumptionoffoodsfromapprovedgeneticallymodiÞedcrops.However,mostofthesafetyandallergenicityassessmentsarebasedonexistingknowledgeofknownallergenicstructures(ie,cross-reactivity),andthereisnowaytopredictwhethernovelproteinswillbecomeallergenicdenovo;simi-larly,thereisnoreliablewaytoassessthesafetyofengineeredfoodsthathavebeenmodiÞedwiththeintentofcreatingaÔÔhypo-allergenicÕÕalternative.SECTIONII:MUCOSALIMMUNERESPONSESINDUCEDBYFOODSSummaryStatement9:ManagenonÐIgE-mediatedreactionstofoodswithappropriateavoidanceandpharmacotherapyasindi-catedwiththeunderstandingthatthespeciÞcroleofimmunity(eg,IgA,IgM,IgG,andIgGsubclasses)intheseformsoffoodal-lergyhasnotbeendemonstrated.[Strengthofrecommendation:Strong;BEvidence]Delayedgastrointestinalreactionsincludeeosinophilicesophagi-tis(EoE),eosinophilicgastroenteritis,eosinophilicproctocolitis,andfoodproteinÐinducedenterocolitissyndrome(FPIES).93-98Delayed-typehypersensitivityreactionscanbetriggeredbymanyfoodsbutmostcommonlycowÕsmilk,soy,wheat,andegg.93-95,99,100Autoimmunemucosaldiseasetriggeredbyfoodantigensincludeceliacdisease.IgAanti-gliadinandanti-endomysial(transglutaminase)antibodieshavebeenstudiedextensivelyingluten-sensitiveenteropathy.Inpart,thepresenceofanti-gliadinantibodiesstronglysuggeststhatgluten-sensitiveenteropathyisduetoadietaryelement.BothserumandsecretoryspeciÞcIgAtodietaryproteinscanbeproducedinhealthysubjectsandallergicpatients,andthisdoesnotpredictallergystatus.InsomeinstancesthelevelsofthelocalsecretoryIgAsubclassmightbeincreasedintheabsenceofmeasurablelevelsofserumIgA(primarilyIgAOralinges-tionofmicroparticlesthatcontaindietaryproteinsleadstoenhancedsynthesisofIgAsecretoryantibodiescomparedwithsolubleproteinsalone.Theroleofcellularinvitrocorrelatesasdiagnosticorprog-nosticindicatorsoffoodallergyiscurrentlyunderinvestigation.Basophilandeosinophilicreactivitytestshavebeenshowntobeassociatedwithfood-inducedallergicresponsesandhavebeenshownincurrentresearchtobemodiÞedovertimeduringimmu-notherapy.Indexesofcell-mediatedimmunity,suchaslymphocyteproliferation,havebeenimplicatedaspossiblecorre-latesoffoodhypersensitivity,withrelativelygreaterproliferationseeninpatientswithfoodallergy,buttheseassaysarenotspeciÞc.TheroleofspeciÞccytokineproÞlesinserumorperipheralmononuclearcellsofpatientswithfoodallergyremainsunderstudyandhasnotbeenwellestablishedtodate.ThereissomeevidencesuggestingtheinteractionofIL-4versusIL-5inimmediateversusdelayedfood-relatedallergicdiseases.SECTIONIII:THECLINICALSPECTRUMOFFOODALLERGYTheclinicianshouldbeawarethatadversereactionstofoodcanbebestcategorizedasthoseinvolvingimmunologicornonimmunologicmechanisms,assummarizedinFigE1AfoodallergyisdeÞnedasanadversehealtheffectarisingfromaspeciÞcimmuneresponsethatoccursreproduciblyonexposuretoagivenfood.ThetermfoodallergyincludesclinicalconditionsassociatedwithalteredimmunologicreactivitythatmightbeeitherIgEmediatedornon-IgEmediated.AlthoughfoodallergyismostoftencausedbysIgE-mediatedreactions,itcanalsobetheresultofreactionsthatareimmunologicbutthroughnonÐIgE-inducedmechanisms(eg,foodproteinÐinducedenteropathyandsomeallergicgastrointes-tinaldisorders,suchasallergiccolitisandproctocolitis).disorders,suchasatopicdermatitisandEoE,oftenhavecharac-teristicsofbothmechanismsandarethereforecategorizedasmixedIgEandnonÐIgE-mediatedconditions.WithnonÐIgE-mediatedfoodallergy,foodsensitizationcannotbedemonstratedbasedonthedetectionoffoodsIgE,andthediagnosisisthereforetypicallybasedonacombinationofreproducibleclinicalsignsandsymptomsconsistentwithtruefoodallergyoccurringonJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL exposuretoafood,resolutionofthosesignsandsymptomswithspeciÞcfoodavoidance,and,insomecases,histologicevidenceofanimmunologicallymediatedprocess,suchaseosinophilicinßammationofthegastrointestinaltractthatresolveswithfoodavoidance.CategoriesofadversefoodreactionsNonimmunologicreactionstofood(foodintolerances)canincludemetabolic,pharmacologic,toxic,and/orundeÞnedmech-anisms.Becausefoodintolerancescansometimesmimicre-actionstypicalofanimmunologicresponse,itisimportanttokeepthesemechanismsinmindwhenevaluatingpatientsreportingadversefoodreactions.Anadversereactiontomilk,forexample,mightbeduetoanimmunologicresponsetomilkproteinoranintolerancecausedbyaninabilitytodigestlactose.Mostadversereactionstofoodadditives,suchasartiÞcialcolorsandvariouspreservatives,havenodeÞnedimmunologicmechanismsandaremostappropriatelycategorizedasfoodintolerancesifreproduciblereactionsdooccur.Othercommonfoodintolerancesincludethoserelatedtopharmacologic(eg,caffeine)ortoxic(eg,scromboid)effectsoffood,whereasforothers,noclearmechanismormechanismshavebeendeÞned(eg,sulÞtes;seeÔÔSectionVI:Diagnosisoffoodallergy,differentialdiagnosis,anddiagnosticalgorithmSummaryStatement10:Determinewhetherthereportedhis-toryoffoodallergy,whichoftenprovesinaccurate,andlaboratorydataaresufÞcienttodiagnosefoodallergyorwhetheranoralfoodchallenge(OFC)isnecessary.[Strengthofrecommendation:Strong;AEvidence]SensitizationaloneisnotsufÞcienttodiagnosefoodallergybecausesubjectscanhaveimmunologicsensitization(asevi-dencedbythepresenceofallergensIgE)tofoodallergenswithouthavingclinicalsymptomsafterexposuretothosefoods.AsdetailedinSection,testingforthepresenceoffoodallergensIgEintheformofskinorinvitrolaboratorytestingishighlysensitive(ie,lowrateoffalse-negativeresults)butonlymoderatelyspeciÞc(higherrateoffalse-positiveresults)andmustalwaysbeselectedandinterpretedinthecontextofthepa-tientÕsspeciÞcclinicalhistory.ThedetailsofthehistoryareusedtogenerateanestimateofthepatientÕslikelihoodofhav-ingtruefoodallergy.ThegeneralsensitivityandspeciÞcityofskinprickorinvitrotestingforthediagnosisoffoodallergyareestimatedtobegreaterthan90%andapproximately50%,respectively.Giventhelowpredictivevalueofboththehistoryandtestresults,itisimportantthatallsuspectedfoodallergybeconÞrmedbyusingappropriateevaluation.DeÞnitionsofspeciÞcfood-inducedallergicconditionsTheclinicianshouldbeawarethatgastrointestinalfoodallergiesincludeaspectrumofdisordersthatresultfromadverseimmunologicresponsestodietaryantigens.AlthoughtheremightbesigniÞcantoverlapbetweentheseconditions,severalspeciÞcsyndromeshavebeendescribed.ThesearedeÞnedasfollows:ImmediategastrointestinalhypersensitivityreferstoanIgE-mediatedfoodallergyinwhichuppergastrointestinalsymptomscanoccurwithinminutesandlowergastrointes-tinalsymptomscanoccureitherimmediatelyorwithadelayofuptoseveralhours.Thisiscommonlyseenasamanifestationofanaphylaxis.Amongthegastroin-testinalconditions,acuteimmediatevomitingisthemostcommonreactionandtheonebestdocumentedasIgEisaclinicopathologicdiagnosisthatrequiressymp-tomsrelatedtoesophagealdysfunctionandisolatedeosin-ophilicinßammationoftheesophagus.EoEiscommonlyassociatedwiththepresenceoffoodsIgE,theprecisemechanisticroleoffoodallergyinitscauseisnotwelldeÞned,andbothIgE-mediatedandnonÐIgE-mediatedmechanismscanbeinvolvedinthepath-ogenesisofthisdisease.InyoungerchildrenEoEpresentswithfeedingdisorders,vomiting,reßuxsymptoms,andabdominalpain,whereasinadolescentsandadultsEoEmostoftenpresentswithdysphagiaandesophagealfoodEosinophilicgastroenteritis(EGE)islesscommonthanEoE,whichisalsobelievedtobebothIgE-mediatedandnonÐIgE-mediatedandoccasionallylinkedtofoodal-lergies.EGEdescribesaconstellationofsymptomsthatvarydependingontheportionofthegastrointestinaltractinvolvedandapathologicinÞltrationofthegastroin-testinaltractbyeosinophilsthatmightbequitelocalizedorverywidespread.Commonsymptomsincludevomiting,abdominalpain,diarrhea,andfailuretothrive/weightloss.MultiplefoodallergensareoftenimplicatedinthisDietaryprotein-inducedproctitis/proctocolitispresentsininfantswhoseemgenerallyhealthybuthavevisiblespecksorstreaksofbloodmixedwithmucusinthestool.IgEtospeciÞcfoodsisgenerallyabsent.Milkproteinismostcommonlyimplicated,althoughmulti-plefoodallergenscanbeinvolved.Symptomswillresolvewithdietaryavoidance,whichmightincludematernaldie-taryrestrictioninbreast-fedinfants.Thisconditiontypi-callyresolvesduringinfancy.isanothernonÐIgE-mediateddisorderthatusuallyoccursinyounginfantsandmanifestsaschronicemesis,diarrhea,andfailuretothrive.Onre-exposuretotheoffendingfoodafteraperiodofelimination,asubacutesyn-dromecanpresentwithrepetitiveprojectileemesisanddehydrationthattypicallyoccurs2to4hoursafteringes-tionoftheoffendingfoodprotein.Pollen-foodallergysyndrome,alsoreferredtoaspollen-associatedfoodallergysyndrome,isaformoflocalizedIgE-mediatedallergy,usuallytorawfruitsorvegetables,andconÞnedtothelips,mouth,andthroat.OASmostcommonlyaffectspatientswhoareallergicto(spe-ciÞc)pollens(eg,ragweedandbirch).Symptomsincludepruritusand/ortinglingofthelips,tongue,roofofthemouth,andthroatwithorwithoutswelling.Systemicclin-icalreactionsarerare.Ithasbeensuggestedthatcolic,gastroesophagealreßux,andconstipationmightbecausedbyfoodallergyinsmallsubsetsofpatients.Additionalevidenceisrequiredtosup-portacausalrelationshipforfoodallergyinpatientswiththesedisorders.TheclinicianshouldbeawarethatrespiratorymanifestationsofIgE-mediatedfoodallergyoccurfrequentlyduringsystemicJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL allergicreactionsandareanimportantindicatorofsevereFoodallergyisanuncommoncauseofchronicrespiratorysymptomsoftheupper(rhinitis)and/orlower(asthma)air-However,acuterespiratorytractreactionsareacommonandpotentiallyfatalmanifestationoffoodallergy.Inpatientswithanaphylaxisandotheracutefood-inducedallergicreactions,res-piratorymanifestationsmightincludenasalcongestion,rhinor-rhea,stridor,tachypnea,laboredbreathing,cough,andwheeze.Severeairwaycompromisecanoccurasaresultoflaryngealedemaand/orbronchospasm,edema,andmucousplugginginthelowerairways,whichcanleadtohypoxiaandairwaycollapse.AsthmaticpatientsappeartobeatsigniÞcantlyincreasedriskofsevereairwaycompromisethatmightresultinfatalandnear-fatalfood-inducedreactions.SECTIONIV:PREVALENCE,NATURALHISTORY,ANDPREVENTIONNaturalhistorySummaryStatement11:ConsiderthenaturalcourseofallergiestospeciÞcfoodswhendecidingonthefrequencyoffoodallergyfollow-upevaluations,recognizingthatallergiestocertainfoods(milk,egg,wheat,andsoy)generallyresolvemorequicklyinchildhoodthanothers(peanut,treenuts,Þsh,andshellÞsh).Theseobservationscouldsupportindividualizedfollow-up(ie,roughlyyearlyre-evaluationsoftheseallergiesinchildhood)withlessfrequentretestingifresultsremainparticularlyhigh(eg,�20-50/L).[Strengthofrecommendation:Moderate;CEvidence]Therateofallergyresolution(naturaltolerance)variesac-cordingtothefood,thepatientÕsage,pathophysiologyoftheallergy,andotherfactorsandisnotwellcharacterizedformostThephysicianshouldbefamiliarwiththenaturalcourseoffoodallergyresolutiontoprovidepatientswithprog-nosticinformationandtodeterminethefrequencyofperiodiclon-gitudinalre-evaluations.Typically,allergytests,suchasskinandserumfoodsIgEtests,aremonitoredtodeterminewhetherim-muneindexesareimproving(eg,lowerfoodsIgElevelsandsmallerskintestresults),asdescribedelsewhereinthisparameter.Onthebasisofstudiesofchildhoodallergies,riskfactorsforpersistenceincludehighinitiallevelsofIgEantibodiesandco-morbidatopicdiseases.NonÐIgE-mediateddisorders,suchasallergicproctocolitisandFPIES,typicallyresolvemorequicklythanIgE-mediateddisorders.Mostchildrenwithfoodallergyeventuallytoleratemilk,egg,wheat,andsoy.Regardingmilk,earlystudiessuggestedresolu-tionratesofapproximately80%byage5years,butamorerecentstudyfromareferralcentersuggestedaslowerresolutionrate:19%atage4years,64%atage12years,and79%byage16years.Roughlysimilarobservationshavebeenmadeforeggallergy,butslightlymorerapidresolutionrateswereobservedforwheat(29%byage4yearsand65%byage12years)andsoy(25%byage4yearsand69%byage10years).Theseobserva-tionscouldsupportroughlyyearlyre-evaluationsoftheseal-lergiesinchildhood,withlessfrequentretestingifresultsremainparticularlyhigh(eg,�20-50kUAllergiestopeanut,treenuts,Þsh,andshellÞshpersistmoreoften,butre-evaluationsarewarrantedbecauselong-termstudiesarelackingandstudiesofchildrensuggestabout20%becometoleranttopeanutand10%resolvetreenutallergy.TherateofresolutionisprobablyslightlylowerforÞshandshellÞshallergy.RecurrenceofaresolvedpeanutallergyisuncommonandappearsmorelikelyamongthosenotincorporatingitintothedietafterresolutionprovedbyOFC(approximatelyOnthebasisofthesedata,periodicre-evaluationofpeanut,treenut,Þsh,andshellÞshallergiesinitiallybylaboratorytestingcanbeconsideredapproximatelyyearlyforyoungchildrenwithfavorabletestresultsandeveryfewyearsorlongerforolderchildrenandadults,dependingonthepatientÕshistoryandtestresults,withmorefrequenttestingifvaluesarebecomingmorefavorablefortolerance.PreventionoffoodallergySummaryStatement12:Encourageexclusivebreast-feedingfortheÞrst4to6monthsoflife.[Strengthofrecommendation:Weak;CEvidence]SummaryStatement13:Forinfantswithafamilyhistoryofatopy,considerapartiallyorextensivelyhydrolyzedinfantfor-mulaforpossiblepreventionofatopicdermatitisandinfantcowÕsmilkallergyifexclusivebreast-feedingisnotpossible.[Strengthofrecommendation:Moderate;BEvidence]SummaryStatement14:DonotrecommendmaternalallergenavoidanceoravoidanceofspeciÞccomplementaryfoodsatweaningbecausetheseapproacheshavenotprovedeffectiveforprimarypreventionofatopicdisease.[Strengthofrecommenda-tion:Weak;CEvidence]SummaryStatement15:Donotroutinelyrecommendsupple-mentationofthematernalorinfantdietwithprobioticsorprebi-oticsasameanstopreventfoodallergybecausethereisinsufÞcientevidencetosupportabeneÞcialeffect.[Strengthofrecommendation:Weak;CEvidence]Recentguidelineshavesuggestedexclusivebreast-feedingforallinfantsregardlessofallergyrisksforgeneralhealthrea-Thereareconßictingdataonwhetherbreast-feedingisprotectiveagainstatopicdisease,butarecentmeta-analysisandarecentlargestudysuggestednosigniÞcantprotectioncomparedwithformulafeeding.Shouldbreast-feedingnotbepossible,guidelineshavesuggestedthatsoyorcowÕsmilkformuladonothaveaprotectiveeffectonatopicdisease,particularlyatopicdermatitis,orfoodallergybutthatsubstitutionwithahydrolyzedinfantformulacanbeconsideredasastrategyforthepreventionoffoodallergy(milkallergyspeciÞcally)oratopicdermatitisforinfantsatrisk,whoaretypicallydeÞnedbyhavingaparentorsiblingwithanatopicdisease.Thedatasup-portingtheserecommendationsarelimitedandsometimescon-andincludethepossibilitythatanextensivelyhydrolyzedformulamightbemoreeffective,butcostandtastefactorsareadditionalconsiderations.Regardingmaternalavoidancedietsduringpregnancyorlactation,therearesomeconßictingdata,butingeneral,thereisinsufÞcientevidencethatmaternaldietduringpregnancyorlactationaffectsthedevelopmentoffoodallergy.Expertsrecommendthatintroductionofsolidfoods,includingpotentiallyallergenicfoods,shouldnotbedelayedbeyond4to6monthsofage.Thisrecommendationisbasedinpartonmultiplerecentstudiesthatappeartosupportdelayedintroduc-tionofallergens,suchasegg,milk,wheat,andpeanut,aspossibleriskfactorsforallergytothefoodsoratopicdisease.How-ever,theserecommendationsaremadeinthecontextofprimaryprevention,andthetimingofaddingadditionalallergenstotheJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL dietofaninfant/childwithaknownfoodallergyhasnotbeenspe-ciÞcallystudied.Infantsorchildrenwith1foodallergymightbeathigherriskforotherfoodallergies,andsomecautionisneededwhenadvancingthediet.Thusfeedingrecommendationsforinfants/childrenregardingprimarypreventionoffoodallergymightbedifferentfromthosesuggestedforchildrenwithanes-tablishedfoodallergy,andthisremainsunexplored.Althoughexpertrecommendationsaddresspreventionstrate-giesregardingbreast-feeding,maternaldietduringpregnancy/lactation,timing/selectionofintroductionofcomplementaryfoods,anduseofselectedsupplementalinfantformulas,therelativeeffectofthesestrategies,individuallyorincombination,hasnotbeenfullyestablishedincontrolledtrials.Theuseofprebiotics,probiotics,orsynbioticsasanactivemeanstopreventfoodallergyoratopicdiseaserequiresadditionalstudy.Manystudies,primarilyonprobiotics,havebeenpub-lished,butcomparabilityislimitedbytheselectionofprobiotic,dose,lengthoftherapy,outcomemeasures,targetpopulation,andotherdifferencesinmethodology.Twometa-analysesonpro-bioticsconcludedthattheymightreducetheriskofeczema,buttherewasnoeffectonotheratopicconditions,andinconsis-tencyamongstudieswasnoted.Studieshavegenerallynotshownapreventiveeffectonfoodsensitizationorallergy,althoughpowertodosoisgenerallylacking.Therearefewpreventionstudiesonprebioticsandsynbioticsthatalsosup-portapossiblebutinconsistentpreventioneffectonatopicderma-titiswithoutaddressingornotshowingeffectsonfoodallergy/Physiciansshouldbeawarethatprobioticscancontainmilkproteins.SECTIONV:ADVERSEREACTIONSTOFOODADDITIVESFoodadditivesaredeÞnedassubstancesaddedtofoodsduringprocessingtoimprovecolor,texture,ßavor,orkeepingqualities;examplesincludeantioxidants,emulsiÞers,thickeners,preserva-tives,andcolorants.MostfoodadditivesareidentiÞedontheingredientlabel;however,thereareanumberoffoodadditivesthatareÔÔgenerallyregardedassafeÕÕbytheUSFoodandDrugAdministration,andthesearenotrequiredtobelistedonlabels,althoughfoodmanufacturersmightlistthem.Foodadditivescanbechemicalsornaturalfactors(derivedfromplantoranimals).Thematerialsaddedtofoodincludepreservatives,emulsiÞers,stabilizers,acids,nonstickagents,humectants,Þrmingagents,antifoamingagents,coloringsandßavorings,solvents,antioxidants,ßavorenhancers,andevennutritivematerials,suchasmineralsandvitamins.SummaryStatement16:Donotroutinelyrecommendthatpa-tientswithchronicidiopathicurticaria(CIU)avoidfoodscontain-ingadditives.[Strengthofrecommendation:Strong;BEvidence]AlthoughthecauseofCIUisunknown,thereisanunderlyingautoimmunepathogenesis(ie,anIgGantibodydirectedagainstthehigh-afÞnityIgEreceptor,anti-Fc,ortheFcregionofIgEanti-IgE)inasigniÞcantnumberofsubjects.166,167Althoughthecauseremainstrulyidiopathicinmanycases,therearenoconvincingdatathatdemonstratethatCIUcanresultfromanallergicreactionorsensitivitytofoodorfoodadditives.Althoughearlierstudiesreportedthatoralchallengeswithanumberofcommonlyusedfoodadditivesprovokedurticariainpatientswithchronicurticaria,thesestudieshadanumberofdesignßaws.Theirdesignsincludedcompletelackoforpoorcontrolsand/orusedsubjectivenonurticarialreactionsorsimplythepresence/increaseofhivesasendpointsforapositivechallengeoutcome.Timepointsforapositivereactioncouldbeaslongas24hoursormore.Whenonealsoconsidersthatantihistamineswerewithheldbeforechallenge,itmakesinterpretationofpositiveresultsdubious.Arecentoraldouble-blind,placebo-controlledfoodchallenge(DBPCFC)studywithcommonfoodadditivesinpatientswithCIUusingsemiquantitativeskinscoresastheendpointproducedpositivereactionsatrateslittledifferentthanthoseseenwithplacebo.168Themostrecentstudy,usingsemi-quantitativeskinscoresastheendpoint,concludedtheprevalenceoffoodadditivesensitivityinCIUpatientsoccursrarelyifatall.169Theseincludechallengeswithmonosodiumglutamate(MSG),benzoates,para-bens,sulÞtes,butylatedhydroxyanisole/butylatedhydroxytoluene(BHA/BHT),tartrazine(FD&CYellow#5,E102),Sunsetyellow(FD&CYellow#6,E110),andaspartame(Nutrasweet).CliniciansshouldnotrecommendtheirpatientswithCIUavoidfoodscontainingadditives.SummaryStatement17:DonotroutinelyinstructasthmaticpatientstoavoidsulÞtesorotherfoodadditivesunlesstheyhaveapriorreactiontosulÞtes.SulÞtesaretheonlyfoodadditiveprovedtotriggerasthma.Althoughthesereactionscanbesevere,evenlife-threateninginsensitivesubjects,theyarerare.[Strengthofrecommendation:Strong;BEvidence]SulÞte-sensitiveasthmaisawell-recognizedbutrareconditionaffectinglessthan5%ofasthmaticpatients.Thesepatientsusuallyhaveseveresteroid-dependentasthma.Suchasth-maticpatientsgenerallyhaveahistoryofreactionstosulÞtedfoods,suchasdriedfruitorwine.Thereactionscanbesevereandevenlife-threatening.Ifclinicallyindicated,testingwouldbebymeansoforalchallenge.ThesereactionsarenotIgEmediated,andthereforeskintestingisnotindicated.However,otherfoodadditiveshavenotbeenshowntoprovokeasthmaticreactionsinDBPCFCs,andthusneitheroralchallengesnoravoidanceisrecommended(includingtartrazine[FD&CYellow#5,E102],MSG,benzoates,parabens,BHA/BHT,Sunsetyellow[FD&CYellow#6,E110],andaspartame[Nutrasweet]).SummaryStatement18:Considernaturalfoodadditivesintheevaluationofpatientswithahistoryofunexplainedingestant-relatedanaphylaxis.[Strengthofrecommendation:Moderate;CEvidence]SummaryStatement19:Patientswhoexperienceanadversereac-tiontofoodadditivesshouldbeevaluatedforsensitivitytoannattoandcarmine.[Strengthofrecommendation:Strong;AEvidence]Cliniciansneedtorecognizethatthenaturalfoodadditivesannatto(yellow)andcarmine(red)havebeenassociatedwithTheymustalsobecognizantthatthefollowingadditiveshavebeenreportedtocauseanaphylaxis:erythritol,guargum,psyllium,carrageenan,lupine,pectin,gelatin,mycoprotein,andcertainspices.Thusnaturalfoodadditivesandspicesshouldbeincludedinthework-upofpatientswithahistoryofunexplainedanaphylaxis.SummaryStatement20:Cliniciansshouldbeawarethatavoidancemeasuresareappropriateforpatientswithhistoriescompatiblewithadversereactionstoanadditiveuntildiagnosticevaluationcanbeperformed.[Strengthofrecommendation:Moderate;CEvidence]Despitethemanystudiesthatdemonstratealackofassociationbetweenfoodadditivesandallergicreactions,therehavebeenisolatedcasereportsconÞrmedbywell-designedDBPCFCsofreactionstosomefoodadditives.Theseinclude,butarenotJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL limitedto,urticariaandanaphylaxisfromsulÞtes,2studieswithpositiveSPTresponsesbutnooralchallenges,angioedemafromMSG,andurticariafromBHA/BHTThereforeifanotherwisehealthypatientorapatientwithCIUorasthma,forexample,presentswithagoodhistoryofareactiontoafoodadditive,oneshouldstillconsideravoidanceuntildiagnostictesting(skinororalchallenge)canbeperformed.SummaryStatement21:Cliniciansshouldnotrecommendfoodadditiveavoidanceintheirpatientswithhyperactivity/attentiondeÞcitdisorder.[Strengthofrecommendation:Strong;AEvidence]AnecdotalreportsandnoncontrolledorpoorlycontrolledeliminationdietorchallengestudieshavesuggestedalinkbetweenfoodadditivesandattentiondeÞcithyperactivitydisorder(ADHD).However,inaveryrecentlypublishedmeta-analysisofwell-controlleddouble-blindeliminationdietsand/orchallengestudiesofadditivesinpatientswithADHD,althoughtherewasasmallchangeinparentalreportsofsymptoms,nosigniÞcantchangesinteacher-reportedsymptomswerefound.Additionally,neithertheAmericanAcademyofPediatricsnortheUnitedKingdomÕsNationalInstituteforHealthandClinicalExcellenceguidelinesrecommendroutineeliminationdietsforthetreatmentofADHD.SECTIONVI:DIAGNOSISOFFOODALLERGY,DIFFERENTIALDIAGNOSIS,ANDDIAGNOSTICALGORITHMDiagnosisofIgE-mediatedfoodallergySummaryStatement22:Theclinicianshouldobtainadetailedmedicalhistoryandphysicalexaminationtoaidinthediagnosisoffoodallergy.[Strengthofrecommendation:Strong;DEvidence]Theevaluationofthepatientwithsuspectedfoodallergyshouldincludeadetailedmedicalhistorythatconsidersthesymptomsindicativeofvarioustypesofadversereactionstofoods,includingotherimmunologicandnonimmunologicfoodreactions(FigE1),theepidemiologiccharacteristicsofpotentialtriggers(seeÔÔSectionI:ClassiÞcationofmajorfoodallergens,cross-reactivities,geneticallymodiÞedfoods,andclinicalimplicationsÕÕ),andevaluationofthetemporalrelation-shipbetweenfoodingestionandonsetofsymptoms.IgE-mediatedfoodallergymostoftenpresentswithimmediatesymptoms(within2hours)afteringestionoftheculpritfood,themedicalhistorycanprovideimportantcluesthatwillaidintheidentiÞcationofsuspectedfoodallergensandfocusthediagnosticevaluationontheallergenorallergensmostlikelyrelatedtoreportedsymptoms.AlthoughthemedicalhistorylackssufÞcientsensitivityandspeciÞcitytomakethediagnosisofIgE-mediatedfoodallergy,historicalaspectsoffoodreactionscancertainlyaidinidentiÞca-tionofsuspectedallergensandhelpdeterminewhetherotherfac-torsplayaroleinthepresentationofsymptoms.TheclinicianshouldconsiderfoodsthatconsistentlyelicitsymptomsoffoodallergytoimprovetheaccuracyofdiagnosingIgE-mediateddis-Theclinicianshouldalsoascertainhistoricalaspects,suchasthequantityingested,preparationofthesuspectedfood,andfrequencyofsymptomsassociatedwithingestion.Foodsthathavebeeneatenonmultipleoccasionsandhistoricallytoleratedarelesslikelytobecausalfoods;however,theingestionofsubthresholddosesorcertainpreparations(eg,extensivelybakedorfermented)mightresultiningestionofafoodallergenwithoutReviewofthehistoryshouldtakeintoconsider-ationhiddenorunidentiÞedfoodallergensinprocessedfoods,andreviewoffoodlabelsmightbeneededtoidentifypossiblefoodallergensingestedatthetimeofthereaction.Themedicalhistorymightalsorevealotherspecialcircumstancesthatresultinsymptomsafteringestion,suchastemporallyrelatedalcoholconsumption,medicationdosing,exercise,orotheractivities.InadditiontoaidingintheidentiÞcationofsuspectedfoodallergens,adetaileddescriptionofsymptomsisanotherimportantaspectofthemedicalhistorythatcanassisttheclinicianindeterminingwhethersymptomsareelicitedbyIgE-mediatedorothermechanisms.Therearenopathognomonicsymptomsforfoodallergy,andthereisconsiderableoverlapbetweenfood-relatedallergicdisorders(seeÔÔSectionIII:TheclinicalspectrumoffoodallergyÕÕ);however,certainhistoricalaspectsmakethediagnosisofIgE-mediateddiseasemorelikely,suchastheimme-diateonsetoforopharyngealsymptomsorskinabnormalities(eg,pruritus,ßushing,orurticaria)afteringestionofasuspectedfoodallergen.Also,foodshavebeenimplicatedasthemostcommontriggerofanaphylaxis,particularlyamongchildrenthereforeahistoryconsistentwithanaphylaxisorimmediatemultisystemsymptomsafterfoodingestionishighlysuggestiveofadiagnosisofIgE-mediateddisease.ThephysicalexaminationofthepatientwithsuspectedIgE-mediatedfoodallergymightrevealsignsofanacuteallergicreaction(TableE2)orchronicÞndingsconsistentwithallergicdiatheses;however,thephysicalexaminationalonecannotbeconsidereddiagnosticoffoodallergy,andphysicalexamina-tionÞndingsshouldbeconsideredwithinthecontextofthepatientÕsindividualmedicalhistory.Findingsonexaminationinconjunctionwiththemedicalhistoryareimportantindeterminingthemostusefuldiagnostictestortests.Evidenceofatopy,suchasasthma,allergicrhinitis,oratopicdermatitis,mightindicateanincreasedriskofIgE-mediatedfoodallergy.Conversely,physicalÞndingsrelatedtootherdisorders,suchasfailuretothriveordermatitisherpetiformis,mightindicateothernonÐIgE-mediated,autoimmune,ornonimmunologicdisease.WhenconsideringthemedicalhistoryandphysicalÞndings,theclinicianshouldbeawareofseveraladversefoodreactionsorotherallergicdisordersthatareoftenmisclassiÞedasIgE-mediatedfoodreactions.ItisimportanttoruleoutotherclinicalentitiesandaccuratelydiagnoseIgE-mediatedfoodallergybecausethenaturalhistory,severityofclinicalreactivity,anddiseasemanagementvaryforeachdisorder.ClinicalsyndromesthatareoftenmisclassiÞedasIgE-mediatedfoodallergyincludethefollowing:A.allergicreactionscausedbymedicationsorinsectstingsthatcoincidentallyoccuratthetimeoffoodingestion/B.metabolicdisorders(eg,lactoseintolerance);C.toxicreactions(eg,foodpoisoningcausedbyscromboidÞshtoxinorbacteria,suchasspecies,orEscherichiacoliD.chemicaleffects(eg,gustatoryrhinitiscausedbyhot/spicyE.auriculotemporal(Frey)syndromeorgustatoryßushingsyndromecausedbyfoodsF.pharmacologicreactions(eg,caffeine,tryptamine,orJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL G.irritantreactions,particularlyinpatientswithatopicH.infectioussyndromes(eg,Staphylococcusaureustoxinorurticariaduringconcurrentviralinfection);orI.other/idiosyncraticreactions(eg,sulÞtes,nitrites,orMSG).TheclinicianshouldsuspectIgE-mediatedfoodallergyinpatientswithanaphylaxisorallergicsymptomswithinminutestohoursafteringestionofaspeciÞcfoodordelayedreactionsinselectedpersonsgivenadiagnosisofmixedIgE/nonÐIgE-mediateddisorders,suchasatopicdermatitisorEoE.IgE-mediatedallergicreactionshavevariedpresentationsandcaninvolve1,2,ormultipleorgansystems(TableE2).IgE-mediatedsymptomstypicallyoccurimmediatelytoafewminutestohoursafteringestionofthecausativefood.ThemajorityofIgE-mediatedfoodreactionsinvolveskinmanifestations,suchasurticaria,angioedema,orerythema(ßushing).However,theclinicalpresentationandseverityofIgE-mediatedreactionscandependonseveralfactors,includingindividualpatientcharacter-istics,suchasunderlyingcomorbidconditions(eg,asthma),cur-renthealthstatus(eg,concurrentupperrespiratorytractinfectionoruncontrolledatopicdermatitis),activitiesproximatetotheingestionofthecausativefood(eg,exerciseoralcoholconsump-tion),doseand/orpreparationofthecausativefood,anduseofvariousmedications(eg,antihistamines).Fatalandnear-fatalre-actionshavebeenreportedtobecausedbyfoodallergy,andthesereactionshavebeenrelatedtoanumberoffactors,includingadolescentage,underlyingrespiratorydisease(eg,asthma),concomitantuseof-blockermedications,reactionsthatdonotinvolvetheskin,anddelayedtreatmentorfailuretotreatwithMixedreactionsinvolvingbothIgE-mediatedandnonÐIgE-mediated(cellular)mechanismscanbedelayedbyseveralhoursorresultinchronicsymptoms(eg,EoEoratopicdermatitis)causedbyingestionofthecausativefoodorfoods.thehistoryoftenlacksdirecttemporalcorrelationbetweenfoodingestionandsymptomonset,thediagnosticevaluationofpa-tientsexperiencingmixedreactionsmightrequireextensivedie-tarydocumentationanddietarymanipulationstoaccuratelyidentifytheculpritfoodorfoods.Dietaryeliminationandreintro-ductionofsuspectedfoodallergenscanbeusefuldiagnostictoolsinpatientswithmixedIgE/nonÐIgE-mediatedfoodreactions.Theclinicianshouldobserveareductioninsymptomswithdietaryeliminationofculpritfoodsandsubsequentrecurrenceofsymp-tomswithreintroduction.SummaryStatement23:TheclinicianshouldusespeciÞcIgEtests(SPTs,serumtests,orboth)tofoodsasdiagnostictools;however,testingshouldbefocusedonfoodssuspectedofprovok-ingthereaction,andtestresultsaloneshouldnotbeconsidereddiagnosticoffoodallergy.[Strengthofrecommendation:Strong;BEvidence]BecauseofthelowPPVofself-reportedsymptomsandlackofpathognomonicsignsonphysicalexamination,theaccuratediag-nosisofIgE-mediatedfoodallergyshouldbeaidedbylaboratoryallergytesting,includingskinprickand/orserumIgEtesting.TheclinicianshouldbeawarethatarelativelysmallnumberoffoodsareresponsibleforthemajorityofIgE-mediatedfoodreac-tions,andthereforepaneltestingtoalargenumberofallergensshouldnotbeconducted.TheselectionofallergensfortestingshouldbeguidedbythepatientÕshistoryofclinicalreactivitytospeciÞcfoodallergensthathaveeitherbeentemporallyrelatedtoacutesymptomsinIgE-mediateddiseaseorfoodsthataresus-pectedtoexacerbatechronicsymptomsinmixedIgE-mediated/nonÐIgE-mediateddisease.Theclinicianshouldalsoconsiderepidemiologicfactorsrelatedtocommonfoodallergens.Forexample,reactionstoshellÞshandpeanutsarealmostalwaysIgEmediated,whereasotherfoods,suchasmilkandsoy,arecommonlyassociatedwithIgE-mediated,nonÐIgE-mediated,andmixedreactions.Forchildrenathighrisk,suchaschildrenwithearlydevelopmentofsevereatopicdiseaseorchildrenwithasibling/parentwithpeanutallergy,sIgEtestingcanbeconsideredbeforeintroductionofcertainfoods.Forthesehigh-riskpatients,theclinicianshouldconsidersIgEtestingforhighlyallergenicfoods,suchasmilk,egg,andpeanut.Peanutallergyhasbeenfoundtobemoreprevalentamongchildrenwithaprimaryrelativewithpeanutallergy,andinacohortofyounginfantswithearlydevelopmentofmilkandeggallergy,investigatorsfounda69%sensitizationratetopeanut.ThereforetestingmightprovidetheclinicianwithimportantdatatoaidindecisionmakingregardingtheneedforOFCsorfoodintroductions.Thereisinsuf-ÞcientevidencetosupportthewidespreaduseofsIgEtestinginchildrenwhoarenotathighriskbecausesuchtestingcanleadtounnecessarydietaryrestrictions.SPTscanbeperformedintheofÞcesettingandrepresentasafeandeffectivemethodofdetectingsIgEantibodies.Althoughstandardizedcommercialextractsarenotavailableandinterna-tionalstandardsforadministeringandinterpretingresultshavenotbeenestablished,SPTsarecommonlyusedtoaidinthediagnosisofIgE-mediatedfoodallergy.Inevaluatingfruitsandvegetables,orincasesinwhichextractsforfoodsarenotavail-able,physiciansmightuseaprick-prickmethodwiththefreshfoodoraslurrymadewiththefoodandsterilesaline.Resultsareinterpretedbycomparingtheskinresponsewithnegative(eg,saline)and/orpositive(eg,histamine)controls.ApositiveSPTresponsewillproduceawheal-and-ßarereactionwithin10to20minutesafterallergenintroduction,andgenerally,anSPTresponseisconsideredpositiveifthewhealhasameandiameter3mmorlargerthanthatelicitedbythenegativecontrol.BecauseapositiveSPTresponseonlyreßectsthepresenceofsIgEboundtothesurfacesofcutaneousmastcells,skintestreactivityshouldnotbeconsidereddiagnosticofclinicalreactivity.SPTsforfoodshavelowspeciÞcity,andpreviousstudieshavereportedPPVsatvariablewhealsizesdependingonthepopulationandfoodbeingstudied.SPTsshouldbecon-ductedonlyforsuspectedfoodallergens,andinterpretationofre-sultsshouldbeconsideredinlightofthepatientÕshistoryofclinicalreactivityinanefforttoreducetherisksofoverdiagnosisandunnecessarydietaryeliminations.Theclinicianshouldrealizethatalthoughwhealsizehasnotbeencorrelatedwithdiseaseseverity,whealsizecanbeusedtoaidinmedicaldecisionmaking.Thelargerthewheal,themorelikelytheallergenistobeclinicallyrelevant.Meandiameterwhealsizecanbeusedasapredictorfororaltolerancedevelopmentforselectedfoods.InastudyexaminingthepredictivevalueofSPT-inducedwhealsizeinchildrenwithadiagnosisofpeanutallergy,investigatorsfoundthatameanwhealsizeof8mmorgreaterwashighlypredictiveofhavingapositivefoodchallengeresulttopeanut(95%PPV).Otherinvestiga-tionshaveestablishedSPTmeanwhealsizecutoffsandPPVsforalimitednumberofcommonfoodallergens(TableThesecutoffscanbeusedtohelptheclinicianJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL establishtheprobabilityofclinicalreactivityversusoraltoleranceanddeterminetheneedforfurthertesting(eg,OFC)ordietarymanipulations.TheclinicianshouldbeawarethatPPVsofwhealsizescanvarywithageorotherfactors,suchasskintestloca-tion(eg,volarsurfaceofforearmvsback),SPTdevice,orre-agents(whicharenotstandardized)usedfortesting.SPTshavearelativelyhighNPVandareparticularlyusefulinrulingoutIgE-mediatedfoodallergytoaspeciÞcfoodduringtheinitialdiagnosticworkupofpatientswithsuspectedIgE-mediatedfoodallergy.However,anegativeSPTresponsedoesnotruleoutclinicalreactivity.Whenevaluatingpatientswithahighde-greeofclinicalsuspicion,theclinicianshouldusefurtherdiag-nostictestsiftheSPTresponseisnegative.Otherdiagnostictests,suchasserumsIgEmeasurementand/orOFCs,shouldbeusedtoaidinthediagnosisbeforeallowingthepatienttoreintro-duceahighlysuspectfoodintothediet.Immediatehypersensitiv-ityskintestingforfoodsisassociatedwithanestimatedsensitivityandspeciÞcityof85%and74%,respectively,andacalculatedpositivelikelihoodratioof3.3.Thisimpliesthatapositiveskintestresultwouldentailarelativelysmalleffectonapretestprobabilityforfoodallergydeterminedbyadetailedhis-tory.Forinstance,inthecaseofapatientwhosepretestprobabil-ityis30%,apositiveskintestresponsewouldleadtoaposttestprobabilityofonly50%.Inusingadiagnostictestwithapositivelikelihoodratiointhisrange,itisimportantforthecliniciantobeawarethatwhenapretestprobabilityforallergytoaspeciÞcfoodisnothighandcertainlywhenthereisnohistorysuggestiveforfoodallergy,apositiveskintestresponsetothatfoodcannotreli-ablyestablishadiagnosisoffoodallergy.SerumsIgEtestingisanotherimportantdiagnostictoolthatcanaidinaccurateidentiÞcationofcausalfoodallergens.Fluorescence-labeledantibodyassaysareusedtodetectthepres-enceofcirculatingIgEantibodiestosuspectedfoods.Althoughusefulindeterminingallergicsensitization,detectionofsIgEalonecannotbeconsidereddiagnosticoffoodallergy.Foodsselectedfortestingshouldbebasedonthemedicalhistoryandepidemiologicfactorsrelatedtofoodallergens.TestingtolargepanelsormultipleallergenswithoutconsiderationofthepatientÕshistoryshouldbeavoidedbecausefalse-positivetestresultscanresultinunnecessarydietaryeliminationofsafefoods.Investigatorshaveestablishedpredictivethresholdsforpeanut,egg,milk,Þsh,soy,andwheat(TableE3andthesecutoffsareusefulindeterminingwhetheranOFCiswarrantedorwhenadvisingpatientsaboutthelikelihoodofclinicalreactivitytothesuspectedfoodallergen.Generally,highersIgElevelsaremorelikelytobeassociatedwithclinicalreactivity,butthepre-dictivevalueofsIgElevelsvariesacrosspatientpopulationsandmightberelatedtothepatientÕsage,timesincelastingestionofthesuspectedfoodallergen,andotherunderlyingdisor-sIgEtestingcanbeusefulintheclinicalsettingwhenthereisahighdegreeofclinicalsuspicionbutnegativeSPTresponses,andsIgEtestingisparticularlyusefulwhenSPTsareprecludedbyongoingantihistaminetherapy,moderate-to-severeskindisease,ordermatographism.TheclinicianshouldbeawarethatnegativesIgEresultsdonotruleoutclinicalallergy.Ifthereisahighdegreeofclinicalsuspicion,othertests,suchasSPTs,anOFCtothesuspectedfood,orboth,mightbewarranted.AdviceregardingreintroductionofapotentialfoodallergencannotrelysolelyonsIgEtestingbecauseoftheriskofaseriousorlife-threateningallergicreaction.ThehistoryofclinicalreactivityalongwithresultsofotherdiagnostictestsareusefuladjunctivetoolswhensIgEtestresultsarenegativeorlessthantheestablishedPPVthresholds.SummaryStatement24:Component-resolveddiagnostictestingtofoodallergenscanbeconsidered,asinthecaseofpea-nutsensitivity,butitisnotroutinelyrecommendedevenwithpea-nutsensitivitybecausetheclinicalutilityofcomponenttestinghasnotbeenfullyelucidated.[Strengthofrecommendation:Weak;CEvidence]Component-resolveddiagnosis(CRD)usesallergenicproteinsderivedfromrDNAtechnologyorpuriÞcationfromnaturalsourcestoidentifythepatientÕssIgEreactivitytorecombinantallergenicproteinsratherthanwholeallergen.CRDisaprom-isingnewdiagnostictoolintheÞeldofallergy;however,furtherinvestigationiswarranted.CRDisnotroutinelyrecommendedforthediagnosisoffoodallergy,butCRDmightbeusefulincertainclinicalscenarios.StudiesoftheclinicalutilityofCRDforspeciÞcallergenshaveshownpromisingresultsforarelativelysmallnumberoffoods.RecentstudiesproposesIgEantibodiestoArah2asthemostcommonpeanutallergenassociatedwithclinicalreactivity,andsensitizationtoArah1,2,or3hasbeenassociatedwithincreasedseverityofreactionsincertainsubjects,especiallycomparedwiththosesensitizedtoArah8(Betv1related),whoexperiencepredominantlyoralallergysymptoms.larly,sensitizationtoCora9andCora14hasbeenassociatedwithbothsymptomseverityandobjectiveÞndingsduringDBPCFCstohazelnut.TheseÞndingssuggestthatCRDcouldpotentiallyenhancediagnosticaccuracyandprovideinsightregardingthenaturalhistoryorseverityrisksforpatients.Howev-er,studieshavebeenlimited,andinconsistenciesexist.AlthoughArah1,2,and3peanutcomponentshavebeenimplicatedasthepredominantallergensrelatedtopeanutallergyincertaingeographicregions,Arah9hasbeenimplicatedasthemajorallergeninothergeographicregions(ie,theMediterraneanInapediatricinvestigationCRDdidnotimprovediag-nosticaccuracyinpredictingeggormilkOFCoutcome,anumberofstudieshavesuggestedthatCRDtestingisinconsis-tentacrossgeographicregionsforotherfoods.studiesareneededtodeÞnetheclinicalutilityofCRDtesting.SummaryStatement25:TheclinicianshouldconsiderOFCstoaidinthediagnosisofIgE-mediatedfoodallergy.[Strengthofrecommendation:Strong;AEvidence]TherearevarioustypesofOFCs,andthetypeofchallengechosenforassessmentofclinicalreactivitydependsonthepotentialforbiasininterpretationofresults.Thetypesoffoodchallengesincludeopen(unmasked),single-blindwithorwithoutplacebo,anddouble-blind,placebo-controlledchallenges.DBPCFCisthegoldstandardandthemostrigoroustypeofchal-AlthoughDBPCFCsreliablypredictclinicalreactivity,theyarelabor-andtime-intensiveprocedures.Single-blindandopenOFCsarefrequentlyusedforclinicaluse.FordiagnosisofIgE-mediatedfoodallergy,gradeddosingduringOFCsisrecom-mended,regardlessofthetypeofchallengeconducted.dosingminimizestherisksofasevereallergicreactionandiden-tiÞesthelowestprovokingdose(dosethreshold).Additionalprac-ticaldetailsregardingselectionofOFCformats,foodpreparation,dosing,andinterpretationofresultsarebeyondthescopeofthispracticeparameterbutarereviewedindetailinaworkgroupreportandPRACTALLconsensusreport.InterpretationofOFCoutcomecanbeaffectedbypatientbias,observerbias,orboth.BlindingormaskingthechallengefoodJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL canbeusedtoreduceoreliminatebias.Thechallengefoodcanbeblindedbymixingwithanotherfoodvehicleorplacingthefoodinacapsule,althoughthelatterapproachmightaffectoutcomesbyeliminatingoralsymptoms.Inthesingle-blindOFCtheobserverknowswhenthechallengefoodisbeingtested,butthepatientdoesnot.Inthedouble-blindchallengethechallengefoodispreparedbyathirdparty,andneithertheobservernorpatientisawareofwhenthechallengefoodisgiven.Placebo-controlledOFCscanbeconductedinasingle-blindordouble-blindfashion.Ifaplaceboisused,thechallengefoodshouldbeadministeredinaformthatmakesitindistinguishablefromtheplacebo.Inasingle-blindOFCthepatientistoldthatfoodswillbeingestedover1ormoresessions,butthepatientisnottoldwhenthechallengefoodwillbegiven.Consecutivesessionscanbeconductedonthesameday(separatedby2hours)orondifferentdays.Becausetheobserverisawareofwhenthechallengefoodisadministered,itisimportantfortheobservertoremainconsistentthroughoutallsessionstoavoiddisclosingwhenthechallengefoodisbeingservedtothepatient.Thischallengeformatcanbeusedincasesthatareconsideredatriskforpatient-relatedbias,suchasanxietyorfearofthechallengefood.Indouble-blindOFCsathirdpartypreparesandcodes2foodsfortesting.The2preparedfoodsconsistof1challengefoodand1placebofoodthatshouldbeindistinguishablefromeachother(eg,puddingvehiclewithandwithouteggproteinpowder).Thecodedfoodsareservedtothepatientinconsecutivesessionsseparatedbyatleast2hours,andthecodeisnotbrokenuntilbothfoodshavebeeningested.IfthepatientexperiencesallergicsymptomsrequiringdeÞnitivetreatment,suchasantihistaminesorepineph-rineduringingestionoftheÞrstchallengefood,testingtothesecondfoodshouldbedeferreduntilalaterdate.ADBPCFCcanbeconsideredforresearchpurposesorforclinicalpurposeswhenanopenorsingle-blindchallengeresultwasambiguous,whenpastsymptomswereprimarilysubjective,orifpatientanxietyissuspectedtoinßuencethechallenge.AnopenOFCisanunmaskedunblindedfeedingofthefoodinitsnaturalform.OpenOFCsarethemostcost-andtime-efÞcienttypeofOFC,buttheyhavethehighestriskforbias.AlthoughanegativeopenOFCresultcandeÞnitivelydetermineoraltolerancetothechallengefood,apositiveopenOFCresultinginsubjectivesymptomsonly(eg,pruritusorthroattightnesswithoutrashorabdominalpain)mightneedtobeveriÞedwithablindedchallengebecauseofpotentialpatientbias.SummaryStatement26:Ifclinicalhistoryisnotconsistentwithanaphylaxis,performagradedOFCtoruleoutfoodallergy.Openfoodchallengeisbothcost-andtime-efÞcient.[Strengthofrecommendation:Moderate;CEvidence]SummaryStatement27:Ifthediagnosisisstillunclearafteropenfoodchallenge,thenrecommendablindfoodchallenge.[Strengthofrecommendation:Moderate;BEvidence]IndecidingonundertakinganOFCfordiagnosticpurposes,theclinicianshouldconsidertheprobabilityoftoleratingthefood(basedonhistoryandtesting),dosingregimen,formoffood,masking/useofplacebos,locationofchallenge,riskofseverereactions,nutritionalstatus,andotherpatient-relatedAtthetimeofinitialdiagnosticevaluation,thedecisiontoconductanOFCshouldbedeterminedbyboththepatientÕshistoryofclinicalreactivityandsIgEtesting.InmanycasesOFCisnotprudentornecessarytomakethediagnosisofIgE-mediatedfoodallergyifthepatienthasanunequivocalandconvincinghistoryofclinicalreactivitytoaknownfoodallergenandpositivesIgEtestresults(SPTorsIgEmeasurement).Furthermore,thepatientÕshistorycantakepriorityoverlabora-toryÞndingsbecauseresultsofsIgEtestingshouldnotbeinter-pretedasabsoluteindicationsorcontraindicationsforconductinganOFCwhenmakingthediagnosisoffoodallergy.OFCscanbeusedtodetermineclinicalreactivitywhenthehis-toryisuncertainandresultsofsIgEtesting(SPTorsIgEmeasure-ment)arenegativeorwhensIgEtestresultsarepositivebutlessthanestablishedpositivepredictivecutoffsforthesuspectedfood(TableE3).OFCscanalsobeeffectiveindeterminingthedevelopmentoforaltoleranceduringthefollow-upofpatientswithestablishedfoodallergy(seeÔÔSectionVII:Managementoffoodallergyandfood-dependent,exercise-inducedÕÕ).PatientsundergoingOFCsshouldbecounseledontherisks/beneÞtsofthefoodchallenge,andinformedconsentshouldbeobtainedbeforeconductingOFCs.ThebeneÞtsofconductingOFCsincludethepossibilityofexpandingthepatientÕsdietiftheOFCresultisnegative.AnegativeOFCresultalsohaspotentialbeneÞtsofdecreasinganxietyrelatedtofearofallergicreactionandimprovingthepatientÕsqualityoflife.Theseimportantfac-torsshouldbeconsideredwhendeterminingwhetheranOFCisTheclinicianshouldconsiderthebeneÞtsofaddingfoodsthatarehighinnutritionalvalueorubiquitousinthepatientÕsdietaryculturewhendecidingonthetimingofOFCs.FoodswithlittlenutritionalvalueorfoodsthatarenotofinteresttothepatientcanbegivenlowerprioritywhenplanningtoconductmultipleOFCs.Forexample,theclinicianshouldconsiderconductinganOFCtomilkbeforeshellÞshinayoungchildwhoisconsideredacandidateforOFCstobothmilkandshellÞshbecauseofincreasednutritionalbeneÞtsofaddingdairyproductsinthedietofayoungchild.InadditiontopotentialbeneÞts,thepatientshouldbemadeawareoftheriskofanaphylaxisduringOFCiforaltolerancehasnotbeenachieved.Becauseoftheriskoflife-threateningsymptomsoranaphylaxis,OFCsshouldalwaysbeconductedunderthesupervisionoftrainedmedicalstaffinahealthcarefacilityequippedtotreatanaphylaxis.ThedecisiontoconductOFCsintheclinicalversushospitalsettingshouldbedeterminedbasedontheseverityofthepatientÕspriorreactiontothefood,epidemiologicrisksassociatedwiththefoodbeingavailabilityofnecessarytoolsintheeventofaseverereaction,andexpertiseofthesupervisingclinician.TheclinicianshouldbeawareofcertainpatientcharacteristicsthatincreasetherisksassociatedwithOFCs,includinghavingahistoryofapreviousseverereactionorhistoryofreactionafteringestionoftraceamountsofthecausalfood.Concomitantmedicalconditions,suchasasthmaorrespiratorytractinfection,shouldbeconsideredbeforeperformingOFCs.OFCsshouldbedelayedordeferredinpatientswithconditionsthatmightobscureinterpretationofOFCoutcomes,suchasuncontrolledurticariaoratopicdermatitis,orfactorsthatmightincreaseriskintheeventofafailedchallenge,suchasunderlyingcardiovasculardisease,difÞcultvascularaccess,orconcomitanttreatmentwithblockersorangiotensin-convertingenzymeinhibitors.PatientswithfoodallergymightbeatincreasedriskforaseverereactionduringOFCsiftheyhaveasthma(regardlessofseverity)oriftheyarebeingchallengedwithafoodthatisfrequentlyasso-ciatedwithfatal/near-fatalreactions.AllfoodallergenshavetheJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL potentialforresultinginanaphylaxis;however,thefoodsmostoftenimplicatedinfatalornear-fatalreactionsarepeanuts,treenuts,milk,Þsh,andshellÞsh.Whendecidingonthetypeofchallenge,patientcharacteristicsandpotentialforbiasshouldbeconsidered.IfthepatientishighlyanxiousaboutingestionofthechallengefoodorthereisahistoryofsubjectiveordifÞculttointerpretsymptoms,ablindedchallengeiswarrantedinanefforttoreducebias.Ifthepatientisayoungchild,blindingmightbenecessarybecauseofrefusaltoeatthefoodinitsnaturalform.Ideally,blindedOFCsshouldbefol-lowedbyanage-appropriatefullserving(openfeeding)ofthechallengefoodinitsnaturalformtoensurethatthefoodwillbetolerated.Theabilitytoconductanopenfeedingimmediatelyaf-teranOFCmightbelimitedinyoungchildrenbecauseofvolumeorrefusaltoeatthefoodinitsnaturalform.SummaryStatement28:EliminationdietsanddietdiariescanbeusedasanadjunctivemeanstodiagnosefoodallergiesbutarenottobedependedonsolelyforconÞrmingadiagnosis.[Strengthofrecommendation:Weak;DEvidence]DietaryeliminationanddietdiariescanbeusedwhenthepatienthasanuncertainorunclearhistoryofclinicalreactivitytofoodorwhensymptomsaresuspectedtobeduetononÐIgE-ormixedIgE/nonÐIgE-mediatedfoodallergy(seeSummaryState-ment42).Intheseclinicalentitiesonsetofsymptomsoftenlacktemporalcorrelationwithfoodingestion,makingtheaccurateidentiÞcationofcausalfoodsmoredifÞcult.DietaryeliminationandreintroductionofthesuspectedfoodorfoodsshouldbeusedtodeterminewhethersymptomsareresponsivetodietaryeliminationofspeciÞcfoodallergensandthuswillassisttheclinicianinidentifyingthecausalfoodorfoods.Dietaryelim-inationsshouldbelimitedto1orafewfoodsduringtheinitialdiagnosticevaluation,andnoncausalfoodsshouldbepromptlyreintroducedinanefforttoavoidnutritionalrisksassociatedwithprolongedandmultipledietaryeliminations.Theclinicianshouldconsidertheeffectandaddresstherelationshipofcomorbidatopicdiseases,suchasatopicderma-titisandasthma,inpatientswithfoodallergies.Thesecomorbiddiseasesmightberiskfactorsforseverereactions(asthma)orexacerbatedbyfood-inducedallergicreactions(atopicFoodallergyoftencoexistsinpatientswithotheratopicdisorders,includingasthmaandatopicdermatitis,andtheclinicianshouldbeawareoftherisksassociatedwiththesecomorbidconditionsinthepatientwithfoodallergy.Atopicdermatitisisacommonskindisorder,andconcomitantfoodallergyispresentinapproximatelyonethirdofchildrenwithmoderate-to-severeatopicdermatitis.Inpatientswithfoodal-lergy,atopicdermatitiscanbeexacerbatedbyandresponsivetodietaryeliminationofculpritfoods.Toaccuratelydi-agnosecausalfoods,theevaluationofpatientswithatopicderma-titismightrequireacombinationofdiagnostictests,includingsIgEtesting,eliminationdiets,andOFCs,becausesymptomsarecausedbymixedIgE/nonÐIgE-mediatedmechanisms,andfoodallergeningestionmightberelatedtobothimmediateandchronicsymptoms.SPTscannotbeperformedinpatientswithuncontrolledatopicdermatitisorpatientswhocannotdiscontinueantihistaminetherapybecauseofunderlyingallergicconditions.shouldnotbeconductedifsymptomsofuncontrolledatopicdermatitis,asthma,orallergicrhinitisarepresentbecausetheseuncontrolledconditionswillobscureinterpretationofOFCoutcomes.Foodallergyisuncommonlyimplicatedasthecauseofuncontrolledasthma;however,underlyingasthma,regardlessofseverity,hasbeenassociatedwithincreasedriskofsevereallergicreactionsanddeathcausedbyfood-inducedallergicreac-Patientswithconcomitantasthmaandfoodal-lergyshouldbeadvisedregardingtheserisks,andtheclinicianshouldconsideruncontrolledasthmaasanabsolutecontraindica-tionforconductingOFCs.WhenconductingOFCsfordiag-nosticpurposes,itisimperativetohavereadilyavailablerescueasthmamedications(short-acting-agonist)intheeventofanallergicreactioninvolvingthelowerrespiratorytractinadditiontoepinephrine.SummaryStatement29:Adiagnosisoffood-dependent,exercise-inducedanaphylaxisshouldbeconsideredwheninges-tionofcausalfoodorfoodsandtemporallyrelatedexerciseresultinsymptomsofanaphylaxis.Theclinicianshouldrecognizethatsymptomsonlyoccurwithingestionofthecausalfoodorfoodsproximatetoexerciseandthatingestionofthefoodintheabsenceofexercisewillnotresultinanaphylaxis.[Strengthofrecommen-dation:Strong;BEvidence]Food-dependent,exercise-inducedanaphylaxisoccurswhenaspeciÞcfoodallergentriggersanaphylaxisafterorduringtemporallyrelatedexercise.Accuratediagnosismightbeobscuredbasedonthefactthatingestionoftheculpritfooddoesnotresultinsymptomsunlessthepatientengagesintemporallyrelatedexercise.Consequently,theclinicianshouldbeawareofthisrelationshipandascertainadetaileddietaryhistoryinpatientspresentingwithexercise-associatedanaphy-laxis.SymptomsareIgEmediated,andspeciÞcallergentesting(SPTorsIgEmeasurement)shouldbeusedtoaidinaccurateDiagnosticOFCscanbecarriedouttofurtherelucidatetheculpritfoodorfoods,andthesechallengesshouldbeconductedinafacilitythathasappropriateequipmentandal-lowsforexerciseafteringestionofthesuspectedfood.SummaryStatement30:Theclinicianshouldconsiderthediag-nosisoforalallergysyndrome(pollen-foodallergy)andobtainspeciÞcIgEtestingtopollensinpatientswhoexperiencelimitedoropharyngealsymptomsafteringestionoffoodantigensthatcross-reactwithpollenantigens.[Strengthofrecommendation:Strong;BEvidence]Pollen-foodallergysyndromereferstoaformoflocalizedIgE-mediatedallergyresultingfromoralcontactoringestionoffoodsthatcross-reactwithhomologouspollenantigens(seetheÔÔCross-reactivityÕÕsubsection).Itisestimatedthatupto76%ofpersonswithpollenallergyalsohavepollen-associatedfoodal-lergysyndrometoatleast1food.Thefoodallergensinvolvedaretypicallyrawfruitsandvegetables(TableE4),andsymptomsaregenerallyconÞnedtotheoropharynx,resultinginpruritusandangioedemaofthelips,softpalate,andoralmucosa.Diagnosisofpollen-associatedfoodallergycanbeaidedbyconÞrmingahistoryofpollenallergywithsIgEtestingandconcomitanthistoryofhavinglocalizedsymptomsafteringestionofcross-reactiverawfoods(fruitsandvegetables).Becausethecross-reactiveproteinsareheatlabile,patientsmightprovideahistoryofbeingabletotoleratethefoodwithoutsymptomsinitscookedform(eg,cannedpeaches).Additionally,patientsmightreportexperiencingmoreprominentsymptomsaftertheassoci-atedpollenseason(priming).DiagnosticSPTswiththesus-pectedfreshfruit(prick-prickmethod)canbeusedtofurtheraidindiagnosis.SPTswithcommerciallyavailablefruitandvegetableextractsaregenerallylessusefulbecausetheallergensJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL areheatlabileandoftenlosepotency,thusleadingtofalse-negativeresults.OFCscanbeconsideredifthediagnosisisuncer-tain;however,resultscanbeaffectedbygrowthconditionsandripeningofthefruitorprocessingthatmightdecreaseordestroytheallergenicityofthefruitorvegetable.InvestigationsofthepredictivevalueofsIgEtothecross-reactivefoodallergenshaverevealedvariableresultsandaregenerallypoorpredictorsofclinicalreactivity.SummaryStatement31:AdiagnosisofIgE-mediatedcontacturticariashouldbeconsideredinpatientswithahistoryofimme-diateurticarialrashatthesiteofcontactwithafoodallergen.[Strengthofrecommendation:Weak;DEvidence]IgE-mediatedcontacturticariaresultsfromcontactwithsub-stancesinfoodsthatinteractwithsIgEboundtocutaneousmastcells.Contactwiththefoodsubstanceleadstoreleaseofhistamineandotherinßammatorymediators,andurticariallesionsdeveloponlyontheareaofskinthatisindirectcontactwiththefood.Occupationalexposuretorawmeats,seafood,rawvegetables,andfruitsareamongthemostcommonfoodsimplicatedincontacturticaria.Adetailedmedicalhistorycon-Þrmingtheabsenceofsymptomswhenthesuspectedfoodisavoided,andpositivespeciÞc(serumorskin)IgEtestresultstothefoodshouldaidinthediagnosis.SummaryStatement32:DonotroutinelyobtaintotalserumIgElevelsforthediagnosisoffoodallergy.[Strengthofrecommenda-tion:Strong;CEvidence]Althoughincreasedinmanypatientswithfoodallergyorotheratopicconditions,totalserumIgElacksbothsensitivityandspeciÞcityregardingspeciÞcfoodallergydiagnosis.ThereisinsufÞcientevidencetosupporttheuseoftotalserumIgEinthediagnosisoffoodallergy,andaninvestigationofthepredictivevalueofsIgEtototalIgEratiofoundnocorrelationbetweentheratioandOFCoutcome.SummaryStatement33:Donotperformintracutaneoustestingforthediagnosisoffoodallergy(seediscussion).[Strengthofrecommendation:Strong;BEvidence]IntradermalskintestingforfoodallergyisnotrecommendedtoaidinthediagnosisofacuteIgE-mediatedfoodallergycausedbyincreasedriskofsystemicreactions.IntradermalskintestingwithfoodextractshasalsobeenshowntohavesigniÞ-cantlyhigherfalse-positiveratescomparedwithSPTs.foreifreliedon,intradermaltestingwouldnotonlyincreasesystemicreactionrisksbutalsoincreaserisksassociatedwithinappropriatediagnosisandunnecessarydietaryeliminationoffoods.OnepossibleexceptiontotheuseofintradermaltestinginIgE-mediatedfoodallergyincludestheuseofintradermaltestingindelayedanaphylaxisassociatedwithhypersensitivitytothecarbohydratemoietyalpha-galfoundinmammalianredmeats.Thissyndromeischaracterizedbydelayedonsetofanaphylacticsymptoms,andSPTsdonotreliablyidentifytheculpritfoodorfoods.SummaryStatement34:Unprovedtests,includingallergen-speciÞcIgGmeasurement,cytotoxicityassays,appliedkinesi-ology,provocationneutralization,andhairanalysis,shouldnotbeusedfortheevaluationoffoodallergy.[Strengthofrecommen-dation:Strong;CEvidence]InsufÞcientevidenceexiststosupporttheuseofanumberofunprovedornonstandardizedproceduresandtests.Examplesofunprovedmethodsincludeallergen-speciÞcIgGmeasurement,cytotoxicityassays,appliedkinesiology,provocationneutraliza-tion,hairanalysis,lymphocytestimulation,gastricjuiceanalysis,measuresofspeciÞcIgAlevels,HLAscreening,typeIIIimmunecomplexlevels,andothers.ThesetestsshouldnotbeusedbecauseresultscanleadtomisdiagnosisormisseddiagnosisofIgE-mediatedfoodallergy,thusleadingtoinappropriateorunnecessarydietaryeliminationoffoods.Suchtestingcanalsoresultindelayofappropriatediagnosticevaluationandmanage-mentofIgE-mediatedfoodallergy.FoodpatchtestingcanbevaluableinassessingfoodtriggersinpediatricpatientswithSummaryStatement35:Althoughroutineuseofatopypatchtests(APTs)fordiagnosisoffoodallergyisnotrecommended,theuseoffoodAPTsinpatientswithpediatricEoEhavebeendemonstratedtobevaluableinassessingpotentialfoodtriggers.[Strengthofrecommendation:Moderate;CEvidence]ThereisinsufÞcientevidencetosupporttheroutineuseofAPTsinthediagnosisoffoodallergy.APTsforfoodallergylackstandardization,andresultsofpreviousstudiesshowwidevariabilityinthesensitivityandspeciÞcityofresults.Thereisnoconsensusamongexpertsregardingtheappropriatereagents,methodology,orinterpretationofresultsofAPTsinthediagnosisofIgE-mediatedfoodallergy.Foodpatchtestingcanbevalu-ableinassessingfoodtriggersinpatientswithpediatricEoE.NonÐIgEmediated:FPIES,allergicproctocolitis,andenteropathyThephysicianshoulduseacarefulanddetailedhistory(includingdietrecords),physicalexamination,responsetothetrialeliminationdiets,andOFCstodiagnosenonÐIgE-mediatedadversereactionstofoods.FPIES,allergicproctocolitis,andenteropathyusuallyaffectyounginfantsandmanifestwithdelayedsymptoms,startingwithinhours(FPIES)todaysandweeks(proctocolitisandenteropathy)afteringestionoftheoffendingfood.Whenthefoodisingestedonaregularbasis,chronicsymptomsdevelop.InpatientswithacuteFPIES,whenfoodisingestedintermittently,symptomsstartwithrepetitiveprojectileemesisin1to3hoursoffoodingestion,followedbylethargy,ashenappearance,andhypothermiainmoreprotractedcases,withincreasedwhitebloodcellandplateletcountsandmethemoglobinemiainseverecases.InpatientswithchronicFPIES,whichisuncommon,recurrentsevereemesis,bloodydiar-rhea,anemiahypoproteinemia,increasedwhitebloodcellcountswitheosinophilia,andfailuretothrivecanbeseen.Allergicproc-tocolitisusuallymanifestswithbloodandmucusinthestoolinanotherwisehealthythrivinginfant;60%ofthesepatientshaveproctocolitiswhilebeingexclusivelybreast-fed.LaboratoryÞnd-ingscanincludeanemia,mildhypoalbuminemia,andFoodproteinÐinducedenteropathyisanuncommonsyndromeofsmall-bowelinjurywithresultingmalabsorptionsimilartothatseeninceliacdisease,althoughlesssevere.FoodproteinÐinducedenteropathypresentswithprotracteddiarrheaintheÞrst9monthsoflife,typicallytheÞrst1to2months,andtypicallywithinweeksafterintroductionofcowÕsmilkformula.Foodproteins,suchassoybean,wheat,andegg,canalsocauseenteropathy.Morethan50%oftheaffectedinfantshavevomitingandfailuretothrive,andsomepresentwithabdominaldistension,earlysatiety,andmalabsorption.Moderateanemia(typicallycausedbyirondeÞciency)ispresentin20%to69%ofinfantswithcowÕsmilkproteinÐinducedenteropathy.Bloodystoolsareusuallyabsent,butoccultbloodcanbefoundin5%ofpatients.MalabsorptionisJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL common;hypoproteinemia,steatorrhea,sugarmalabsorption,anddeÞciencyofvitaminKÐdependentfactorscanbeseen.ThelaboratoryabnormalitiesreportedinpatientswithFPIES,allergicproctocolitis,andenteropathyarenondiagnosticbutprovidesupportiveevidencefortheclinicalmanifestations.Atrialeliminationdietissuggestedtodeterminewhetherchronicgastrointestinalsymptomsareresponsivetodietarymanipulation.DietaryeliminationoftheoffendingfoodresultsinsigniÞcantimprovementinemesisanddiarrheawithinafewdaysinpatientswithFPIESandresolutionofvisiblebloodinthestoolwithinafewdaysinpatientswithallergicproctocolitis.Inpatientswithenteropathy,resolutionofsymptomsoccursusuallywithin1to4weeks,althoughvillousatrophyonbiopsymightpersistforseveralmonths,upto1.5yearsaftersymptomSummaryStatement36:ThephysicianshouldusethepatientÕsmedicalhistory,responsetoatrialofeliminationofthesuspectedfood,andOFCtoestablishadiagnosisofFPIES.However,whenthehistoryindicatesthatinfantsorchildrenhaveexperiencedhy-potensiveepisodesormultiplereactionstothesamefood,adiag-nosiscanbebasedonaconvincinghistoryandabsenceofsymptomswhenthecausativefoodiseliminatedfromthediet.[Strengthofrecommendation:Strong;BEvidence]Intheabsenceofnoninvasivelaboratorybiomarkers,itisrecommendedthataphysician-supervisedOFCbeperformedforaconclusiveinitialdiagnosisofFPIESandforfollow-upevaluationstodeterminewhetherFPIESresolved.Aphysician-supervisedOFCinpatientswithFPIESisconsideredahigh-riskprocedure,withupto50%ofreactionsrequiringtreatmentwithintravenousßuids.FoodssuspectedofprovokingFPIESshouldnotbechallengedathomebecauseofrisksofsevereadversereactionsandshouldbechallengedinamedicalfacility.Althoughtherecentpopulation-basedstudyreportedsuccessfulmanagementofreactionsduringOFCswithoralrehydration,itisadvisabletohaveintravenoushydrationreadilyavailableincaseofseverereactions.ChallengeresultsareconsideredpositiveiftypicalsymptomsandlaboratoryÞndingsarepresent.Symptomsincludeemesis(onsetof1-3hours),lethargy(onsetof1-3hours),and,lessoften,diarrhea(onsetof2-10hours;mean,5hours).Laboratoryvaluesincludeincreasedneutrophil�(3500cells/mL)andfecalleuko-cytecounts,frankoroccultblood,and/oreosinophilcounts.ACBCwithdifferentialshouldbesentbeforeandabout6hoursafterchallengeiftherearesymptoms.Ifdiarrheaispresent,stoolguaiactestscanbeperformed,andstoolsamplescanbesentforfecalleukocyte,redbloodcell,andeosinophilevaluation.OFCsmightnotbenecessaryfortheinitialdiagnosisifthechildpresentswithrecurrentsymptomsoftypicalFPIES(�_reactionswithclassicsymptomsina6-monthperiod)andiswellwhentheoffendingfoodiseliminatedfromthediet.However,subsequentOFCsarewarrantedtodeterminewhetherFPIEShasresolvedandthefoodeliminationdietcanbestopped.ThephysicianshouldbeawarethatsupervisedOFCsarenotusuallynecessaryforthediagnosisofallergicproctocolitisandenteropathy.Consideringthedelayedonsetandchronicnatureofsymptoms,thereintroductionofthesuspectedfoodafteraneliminationdiettrialcanbeusuallyperformedathomeanddocumentedwithasymptomdiaryandstooltestsforoccultbloodorreducingsubstances.However,iffoodsIgEisdetectedbyusingSPTsorserumtests,indicatingthepotentialforanimmediateallergicreaction,orthehistorysuggestsassociatedvomiting,physician-supervisedOFCsmightbenecessarytosafelyreintro-ducethesuspectedfood.InfantsandchildrenwithnonÐIgE-mediatedgastrointestinalfoodallergycanhavefood-sIgEantibodiestothefoodthathistoricallyinducedonlygastrointestinalreactionsandtransitiontoanimmediate-typefoodallergy.SummaryStatement37:TheclinicianshouldbeawarethatagastrointestinalevaluationwithendoscopyandbiopsyisusuallynotrequiredforthediagnosisofFPIESandallergicproctocolitiswithsymptomsthatrespondtoeliminationoftheoffendingfoodandrecurwhenthefoodisreintroducedintothediet.[Strengthofrecommendation:Weak;CEvidence]GiventhedescriptionofthetypicalconstellationofclinicalsymptomsandstrictcriteriaforapositiveOFCresult,endoscopicexaminationisnotgenerallyperformedinpatientswithsuspectedHowever,beforeestablishmentofdiagnosticcriteria,endoscopicevaluationsweredoneinseverelyillinfantswithcowÕsmilkand/orsoyFPIESandrectalbleeding.Theyreportedrectalulcerationandbleedingwithfriabilityofthemucosainmostpatients.Diffusecolitiswithavariabledegreeofilealinvolvementwasreported;inthemostseverecasesprominenteosinophilia,lymphocyticinÞltration,andvillousatrophywasseen.Colonmucosacanbemildlyfriabletoseverespontaneoushemorrhage,andminuteulcerssimilartothoseseeninpatientswithulcerativecolitiscanbefound.CryptabscesseshavebeenidentiÞedinsomepatients.Inpatientswithallergicproctocolitis,therearenostandardacceptedcriteriafordiagnosis.EosinophilicinÞltrationthroughoutthemucosallayers,particularlyinthelaminapropria,ischaracteristic.Thepresenceofgreaterthan60eosinophilsper10high-powerÞeldsinthelaminapropriaisstronglysuggestiveofallergicproctocolitis.Eosinophilsincryptsorinterspersedinthemuscularismucosaearealsohighlyassociatedwithallergicproctocolitis.Themucosalarchitectureisusuallyintact.FoodproteinÐinducedenteropathyisdiagnosedbytheconÞr-mationofvillousinjury,crypthyperplasia,andinßammationonsmall-bowelbiopsyspecimensobtainedfromasymptomaticpatientwhoisbeingfedadietcontainingtheoffendingfoodallergen.GastrointestinalevaluationwithendoscopyandbiopsyisnecessaryfortheconclusivediagnosisofenteropathyandmightberequiredforpersistentseverechronicFPIESandallergicproctocolitisunresponsivetodietarymanipulation.SummaryStatement38:Measurementoffood-speciÞcIgGandantibodiesinserumarenotrecommendedforthediagnosisofnonÐIgE-mediatedfood-relatedallergicdisorders.[Strengthofrecommendation:Strong;BEvidence]Measurementoffood-speciÞcIgGandIgGantibodiesforthediagnosisofgastrointestinalfoodallergydisordersisnotEosinophilicesophagitisSummaryStatement39:Atrialoftwicedailyproteinpumpin-hibitor(PPI)therapyfor8weeksbeforediagnostictestingforEoEisrecommendedtoexcludegastroesophagealreßuxdisease(GERD)andPPI-responsiveesophagealinÞltrationofeosino-phils.[Strengthofrecommendation:Strong;CEvidence]SummaryStatement40:ThediagnosisofEoEshouldbebasedonthepresenceofcharacteristicsymptomsandendoscopicJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL featuresandthepresenceof15ormoreeosinophilsperhigh-powerÞeldquantiÞedbyapathologistusinghematoxylinandeosinstainingofesophagealbiopsyspecimensat400lightmi-croscopy.[Strengthofrecommendation:Strong;BEvidence]EoEisachronic,antigen-driven,predominantlyeosinophilicinßammationthatisisolatedtotheesophagus.ThediagnosisandmanagementofEoErequiresesophagealendoscopywithbiopsytoevaluatethenumbersofeosinophils,aswellasothercharacteristichistologicfeatures,includingbasalzonehyper-plasia,eosinophildegranulation,anddilatedintercellularMultipleesophagealbiopsyspecimensfromatleast2levelsoftheesophagus(proximal,middle,anddistal)shouldbeevaluatedwhendiagnosingEoE.OthercausesofesophagealinÞltrationofeosinophils,includinggastroesopha-gealreßuxdisease,PPI-responsiveesophagealinÞltrationofeo-sinophils,eosinophilicgastroenteritiswithesophagealinvolvement,inßammatoryboweldisease,esophagealinÞltra-tionofeosinophilsassociatedwithceliacdisease,post-Barrettablation,andtracheoesophagealÞstularepair,shouldbeexcludedbeforediagnosingprimaryisolatedEoE.TypicalEoEsymptomsincludedysphagia,abdominaland/orchestpain,poorappetite,andregurgitation.NosymptomispathognomonicforEoE,andsymptomscannotbeusedinisola-tiontodiagnoseEoEbecausevalidatedsymptommetricsarestillunderdevelopment.Typicalendoscopicfeaturesincludepallor,furrows,rings,exudates,narrowing,andstric-tures,butendoscopicfeaturesintheabsenceofbiopsyshouldnotbeusedtodiagnoseEoE.SubjectswithsuspectedEoEshouldbetreatedwithhigh-dosePPIstoruleoutacid-inducedesophagealinÞltrationofeosino-phils.SymptomaticandhistologicresponsesuggestsGERDorPPI-responsiveesophagealinÞltrationofeosinophils.clinicianshouldfollowsubjectswithPPI-responsiveesophagealinÞltrationofeosinophilsclinicallybecauserepeatesophagogas-troduodenoscopywithbiopsymightbewarrantedtoensurethatthePPIresponseisnotatransientphenomenon.TheclinicianshouldrememberthatPPIscanhaveanti-inßammatoryeffectsinadditiontoacid-blockingeffects.EosinophilicgastroenteritisSummaryStatement41:Eosinophilicgastroenteritis(EGE)shouldbeconsideredaconstellationofclinicalsymptomsincom-binationwithgastric,smallintestine,and/orlargeintestineinÞl-trationofeosinophilsatgreaterthanthereportednormalnumbersofgastricandintestinaleosinophils.[Strengthofrecom-mendation:Weak;DEvidence]Therearenoagreeduponhistologicordiagnosticcriteriaforeosinophilicgastritis,enteritis,oreosinophiliccolitis,butclini-ciansshouldconsiderusingtheKleinclassiÞcationofmucosal,serosal,ormuscularistodescribethelocationoftheeosinophilicinÞltrateinpatientswithEGE.ItisrecommendedthattheclinicianfollowpatientswithEGEbecauseitcanbetransient,persistent,orchronicintermittent.EGEsymptomscanincludeabdominalpain,diarrhea,eosinophilicascites,and/ornausea/vomiting.TheclinicianshouldrecognizethatEoEandEGEare2distinctclinicaldiseasesthatlikelyhavedifferentcausesandaremanageddifferently.ThereisnoevidencethatisolatedEoEprogressestoEGE,butEGEcanhaveesophagealinvolvement.SECTIONVII:MANAGEMENTOFFOODALLERGYANDFOOD-DEPENDENT,EXERCISE-INDUCEDANAPHYLAXISTheprimarytherapyforfoodallergyisstrictavoidanceofthecausalfoodorfoods.Thisistrueforalltypesoffoodallergy,includingIgE-mediatedandnonÐIgE-mediatedfoodallergy.ThissectionwilladdressspeciÞcmanagementissuesrelatedtoeachcategoryoffoodallergy.IgE-mediatedfoodallergyiscommonandoftenassociatedwithlife-threateningreactions.Currenttreatmentapproachesfocusoneducationaboutdietaryavoidanceofculpritallergensandprompttreatmentofallergicreactions.Newtreatmentstrategiesareunderinvestigation,includingallergen-speciÞcandnonspeciÞctherapiesthatmightchangetheapproachtotreatingfoodallergiesinthefuture.SummaryStatement42:Prescribeatargetedallergenelimina-tiondietasthetreatmentforknownorstronglysuspectedfoodal-lergy.Educationaboutproperfoodpreparationandtherisksofoccultexposureisessential.[Strengthofrecommendation:Strong;CEvidence]AllergenavoidancedietsshouldbespeciÞcandlimitedtotherelevantfoodsbasedonaconÞrmeddiagnosistominimizetheriskofanallergicreaction.Theprimaryexposuretoafoodallergenformostpatientsisthroughingestion,althoughsomepa-tientscanexhibitsymptomsafterskincontactorinhalationofaerosolizedprotein.Patients,careproviders,andallpersonsresponsibleforpreparingorobtainingfoodsshouldbeeducatedonhowtoreadingredientlabelstoavoidspeciÞcfoodallergens.Educationalmaterialsrelatedtothe8mostcommonfoodaller-gensandgeneralapproachestoavoidanceindifferentsettingsareavailablethroughresources,suchastheFoodAllergy&ResearchandEducationNetwork(www.foodallergy.org)andtheConsortiumofFoodAllergyResearch(www.cofargroup.orgIntheUnitedStates,Canada,Europe,andAustraliafoodlabelinglawsexisttoimprovesafetyforconsumersandrequirefoodmanufacturerstodeclareinplainlanguagethepresenceofcommonallergens(includingegg,milk,wheat,soy,Þsh,crusta-cean,peanut,andtreenuts)oraproductderivedfromthatallergenwhenusedasaningredient.IntheUnitedStatestheFoodAllergenLabelingandConsumerProtectionAct(FALCPA)of2004(http://www.fda.gov/Food/FoodSafety/FoodAllergens)re-quireslabelingoffoodsrelatedtotheÔÔmajorallergens,ÕÕwiththecommonnameslistedwithintheingredientlistorinaseparateÔÔcontainsÕÕlabel.FALCPAappliestofoodsmanufacturedinorimportedintotheUnitedStatesbutnottoagriculturalproductsoralcoholicbeverages.FALCPAdoesnotregulatetheuseofadvisorylabeling,suchasÔÔmaycontainÕÕorÔÔmanufacturedonequipmentwithÕÕthatareoftenusedtodescribepossiblecross-Avoidanceofproductswiththeadvisoryla-belsismostprudentforpatientswithfoodallergy.Cross-contactorcross-contaminationofanallergeninafoodproductisaconcernforfoodpreparationathome,school,orrestaurantsandinothersettings.Examplesofcross-contactincludepoorhandwashing,sharedgrillsorpans,utensilsorequipmentthatarepoorlywashedbetweenuses,useofafryerformultiplefoods,andcontaminatedorpoorlycleanedworkspaces.Theseexamplesresultincontaminationofasafefoodbyafoodallergenthatcanbeavoided.Additionally,hiddenfoodingredients,suchaspeanutbutterusedasaßavorenhancerJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL inchiliornutsinAsianfood,areexamplesthatcanalsoplaceapatientwithfoodallergyatrisk.Lastly,patientswithknowninha-lationalexposureandthosewithoccupationalallergycausedbyfoodsmightneedtofurtheravoidaerosolizedfoodexposureorwearglovesandmasksifalternateemploymentisnotpossible.Youngchildrenmightneedtobesupervisedaroundfoodaller-genstoavoidhandtomouthoreyecontact.Standardcleaningprocedures(wipingorwashingwithsoapywater)sufÞcetore-moveallergensfromsurfacesandhands.Patientsandcaregiversmustbeeducatedaboutappropriatelabelreading,cross-contact,hiddenfoods,andenvironmentalexposureswhenobtainingorpreparingmeals.Whenprescribinganeliminationdiet,theclinicianmustunderstandthedifferencesinpotentialriskamongcross-reactivefoodsandmakeappropriaterecommendations.Dietaryavoidanceoffoodsthatarerelatedandhavepotentiallycross-reactiveproteinsshouldbeindividualizedaccordingtotheriskofclinicalcross-reactivity(seeÔÔSectionI:ClassiÞcationofmajorfoodallergens,cross-reactivities,geneticallymodiÞedfoods,andclinicalimplicationÕÕ).Particularfoods,suchasmilkproteinsources(eg,cowandgoat),treenuts(eg,cashewandpistachio/walnutandpecan),Þshspecies,andshellÞshspe-cies,oftenhavesharedproteincross-reactivity,andpatientswithfoodallergyshouldavoidthefoodclass.Incontrast,thema-jorityofpatientswithpeanutallergycansafelyconsumeotherle-gumes(eg,soyandbeans),despitebeinginthesamefoodfamily.Similarly,patientswithwheatorothergrainallergycanoftenconsumeothergrainswithoutadversesymptoms.Asnotedbelow,somepatientswithpollenallergyarenotabletoconsumerawfruitsorvegetables,butoncecooked,thesefoodscanusuallybesafelyconsumedwithoutcausingsymptoms.Patientswithla-texallergyoftenhavetoavoidfoods,suchasbananas,avocados,orchestnuts,becauseofcross-reactiveproteins.Lastly,mamma-lianredmeats(eg,beef,pork,lamb,andvenison)haveacross-reactivecarbohydratedeterminant,alpha-gal,incommonwithalpha-galfoundinticksaliva.Patientswithpriortickexpo-surecanproduceIgEtoalpha-galthatresultsindelayedanaphy-laxisafterconsumptionofredmeat.Eventhoughsharedclinicalallergyacrossmeatsisgenerallyuncommon,whenalpha-galhy-persensitivityispresent,allmammalianredmeatshouldbeavoided.Theappropriateeliminationdietmustbetailoredtoeachpatient.TheclinicianshouldrecognizethataproperdietcanvaryfromregularexposuretosomemodiÞedproteins(eg,abakedeggÐorbakedmilkÐtolerantpatient)tostrictavoidanceofAlthoughastrictavoidancedietofallallergicfoodsistypicallyrecentstudiesindicatethatregularexposureofheat-modiÞedeggandmilkproteininallergicpatientsisnotonlywelltoleratedinupto70%ofallergicpatientsbutmightbeclin-icallybeneÞcial.Extensiveheating(baking)ofeggandmilkproteinsresultsinconformationalmodiÞcationandreducedallergenicity.Recentdatasuggestthatintroductionofthesefoodsalsoacceleratesdevelopmentoftolerance.Patientswhocansafelyconsumebakedeggandmilkshouldcontinueregularingestionofthesefoods.Forknownallergicpatientswhoarenotconsumingbakedeggormilkproteins,anobservedfoodchal-lengewithaservingportionofamufÞnorotherappropriatefoodiswarrantedtoensuresafeconsumption.Severalrecentstudieshavedemonstratedthattraceeggexposuresinmostinjectableinßuenzavaccinesaregenerallywelltoleratedbypatientswitheggallergy.Onthebasisoftheseresults,currentguidelines,includingafocusedpracticeparam-eter,havebeenrecentlyupdatedtoencourageroutineimmuni-zationofsuchpatientswithouttestingorspecialaccommodation(ie,splitdosingordesensitization).SummaryStatement43:Recommendconsultationwithanutri-tionistforgrowingchildreninwhomeliminationdietsmightaffectgrowth,aswellasthosepatientswithmultiplefoodal-lergies,poorgrowthparameters,orboth.Cliniciansmustbeawareofthenutritionalconsequencesofeliminationdietsandcertainmedications,suchasesomeprazole,especiallyingrowingchildren.SpeciÞcally,identifyingalternativedietarysourcesofcalciumandvitaminDiscriticalforpatientswithmilkallergy.[Strengthofrecommendation:Strong;BEvidence]Whenthehistoryand/ortestresultsdonotclearlyidentifyanIgE-mediatedfoodallergyasthelikelycauseofthepatientÕssymptoms,furtherworkuptoconÞrmtheappropriatediagnosisisthemostcriticalnextstep.Eliminationdietsinsuchascenariomightbeunnecessarilyrestrictiveandnutritionallyharmfulandarenotrecommended.Allergenavoidancedietscanresultinfail-uretothriveand/orvitamin,mineral,ornutrientdeÞciencieswhennotcarefullymanagedorwhenoverlyaggressive.Addressingnutritionalconcerns,suchascalciumandvitaminDintakeforapatientwithmilkallergyorpoorproteinandfatcon-sumptioninachildwithmultiplefoodallergies,requirescloseattentiontodietaryintakewithpatientsoftenbeneÞttingfromconsultationwitharegistereddietitian.Nutritionalcounselingandregulargrowthmonitoringisrecommendedforchildrenwithfoodallergies.TheUSDepartmentofAgricultureregularlyupdatesinformationregardingdietaryrecommendationsthroughwww.usda.govwww.choosemyplate.govSummaryStatement44:ReviewrecognitionandtreatmentofIgE-mediatedfood-relatedallergicreactionswitheachpatientandcaregivers,asappropriate.Emphasisshouldbeplacedonpromptawarenessofanaphylaxisandswiftintervention.[Strengthofrecommendation:Strong;CEvidence]Food-inducedanaphylaxisisaseriousallergicreactionthatisrapidinonsetandcancausedeath.Promptrecognitionofsignsorsymptomsofanallergicreactionisessentialforappropriatemanagement.Symptomscanbeuniphasic,biphasic,orprotractedandcaninvolveallorgansymptoms.Delaysinsymptomrecognitionandappropriatetreatmentcanresultinpooroutcomesafterallergenicfoodingestion.Patients,parents,andallcareprovidersshouldbeeducatedaboutthesignsandsymptomsofanaphylaxis,theimportanceofearlyrecognitionandprompttreatment,andthestepsofactiontopreventandtreatallergicSummaryStatement45:Discussself-caremanagementtech-niques,especiallywithhigh-riskpatients,(eg,adolescents,youngadults,andasthmaticpatients),focusingonriskreductionandrecognitionandtreatmentofanaphylaxis.[Strengthofrecom-mendation:Strong;CEvidence]IgE-mediatedfoodallergyisassociatedwithanincreasedriskofdeathafteraccidentalingestion.Food-inducedfatalitiesaremostcommonlyreportedfromexposuretopeanutsandtreenuts,butsevereandfatalreactionscanoccurwithanyculpritfoodallergen.Fatalitiesareoftenassociatedwithalackofordelayedtreatmentwithepinephrine.Theriskfactorsassoci-atedwithheightenedmortalityincludeteenandyoungadultage,pre-existing/poorlycontrolledasthma,andpreviouslydiagnosedfoodallergy.Otherfactorsincludeanabsenceofskinsymptoms,JALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL patientdenialofsymptoms,concomitantalcoholconsumption,orrelianceonoralantihistaminestomanagesymptomsinplaceofSummaryStatement46:UseepinephrineasÞrst-linemanage-mentforthetreatmentofanaphylaxis.[Strengthofrecommenda-tion:Strong;CEvidence]SummaryStatement47:Ensurethatself-injectableepinephrineisreadilyavailabletothepatientandinstructthepatient,caregiver,orbothontheimportanceofitsuseandself-administration,asrelevant.[Strengthofrecommendation:Strong;CEvidence]IntramuscularepinephrineistheÞrst-linetreatmentinallcasesofanaphylaxis.Allotherdrugshaveadelayedonsetofaction.Repeatepinephrinedosingshouldbeusedwhensymptomsprogressorresponseissuboptimal.SummaryStatement48:Evaluatechildrenwithfoodallergiesatregularintervals(1-2years),accordingtothepatientÕsageandthefoodallergen,todeterminewhetherheorsheisstillallergic.Iffoodallergyisunlikelytochangeovertime,asinadults,periodicre-evaluation(2-5years)isrecommended,dependingonthefoodallergy.[Strengthofrecommendation:Strong;CEvidence]Themanagementoffoodallergyshouldincludeongoingclinicalassessmenttore-evaluatethepatientÕsallergicstatus;monitoringofdietaryallergenavoidance,includinglabelreading/cross-contact/specialsettings,nutritionalstatus,accidentalin-gestions,andassociatedreactions;andoverallconsequencesinvolvingqualityoflifeandeffectonthepatientandhisorherfamily.Theclinicianmustalsoassessforcomorbidities,suchasasthma,atopicdermatitis,andallergicrhinitis.Yearlyeduca-tionisneededtoreinforcetheimportanceofearlyrecognitionandemergencytreatmentofacuteallergicreactions,useofanup-datedemergencyactionplan,andrepeattrainingwiththeepinephrineautoinjector,ifapplicable.Becausethenaturalhistoryoffoodallergyvarieswiththeallergenandthepatient,long-termmanagementshouldincludemonitoringforevidenceoftoleranceorfordevelopmentofnewfoodallergies.Thisincludesobtaininginterimclinicaldataregardingreactionstofoodsand,ifindicated,performingSPTsorallergensIgEtests.Theoptimalintervalforfollow-uptestingisnotknown.Allergytosomefoods,suchasmilkandegg,canbeoutgrownrelativelyquickly,whereasallergytootherfoods,suchaspeanut,treenuts,Þsh,andshellÞsh,aretypicallyTestingevery12to18monthsisrecommendedintheÞrst5yearsoflifetoassessforevidenceoftolerancedevel-opment.Thistestingintervalcanbeextendedtoevery2to3yearsthereafteriflevelsremainhigh.Forallergiestotreenuts,Þsh,andcrustaceanshellÞsh,testingcanbeperformedlessfrequently(every2-4years).ThisintervalcouldbeextendedinadultswithlittlechangeovertimeinsIgElevels.Ifapatienthashadarecentfood-inducedallergicreaction,thenthereislittlereasontoretestduringthe1-to2-yeartimeintervalafterthereaction,de-pendingontheallergenandtheseverityofthereaction.Forexample,anadolescentallergictopeanutswithanincreasedspe-ciÞcpeanutlevelof25kU/Landahistoryofgeneralizedhivesandlaryngealedemawithingestioninthelastyearwouldnotrequiretestingforatleast2to3yearsorlongerbecauseofthelowpossibilityofbecomingtolerantduringthatinterval.Howev-er,forayoungerchild(eg,yearsofage)withthesamepeanutsIgElevelandclinicalreaction,testingevery1to2yearsforseveralyearstodeterminethedecreaseinsIgElevelcanassistinassessingfornaturaltolerancedevelopment.IfapatienthashadaknownfoodallergeningestionwithoutsymptomsorhassufÞcientlyreducedfoodsIgEtestand/orSPTresults,furtherassessmentoftolerancewithamedicallysupervisedOFCmightbewarrantedtoensuresafeadditiontothediet.SummaryStatement49:Forpatientswithfood-dependent,exercise-inducedanaphylaxis,avoidfoodingestionwithin2to4hoursofexerciseforpreventionofsymptoms,andprovideprompttreatmentwithonsetofsymptoms.[Strengthofrecom-mendation:Strong;CEvidence]Food-dependent,exercise-inducedanaphylaxiscanoccurduringorsoonafterexercisethatisprecededbyingestionofacausalfoodallergen.Whetherareactionoccursdependsontheamountoftimebetweenfoodconsumptionandexercise,usuallywithin2and4hours.Wheatandcrustaceansarethemostcom-monfoodculprits,butotherfoodshavebeenimplicated.Managementinvolvesseparationoffoodingestionandexercise,withavoidanceofexercisefor2to4hoursafterallergenicfoodingestion,aswellasprescriptionofepinephrinefortreatmentofacutesymptoms.Whenexercising,patientsshouldbeaccompaniedbyaÔÔbuddyÕÕwhoisawareoftheircondition,carriesacellphone,andisabletomanageanaphylaxis,shoulditoccur.SummaryStatement50:Managepollen-foodallergysyndromeororalallergysyndromebydietaryavoidanceofrawfruits,veg-etables,orbothbasedonthepatientÕssymptomproÞleseverity.Theextentoffoodavoidancedependsontheseverityoforopha-ryngealsymptoms.[Strengthofrecommendation:Strong;CMostpatientswithOASbeneÞtfromcookingrawfruitsandvegetablestodenatureproteinsbeforeingestion.Patientswithmild-to-moderateoralsymptoms,suchaslip/mouthtinglingorswellingorthroatpruritus,areadvisedtocookfoodsbeforeandtocontinueingestingcookedorbakedformsofplantfoods,astolerated.However,ifsymptomsaremorese-vere,progressinseverity,orareassociatedwithsystemicsymp-toms,fulldietaryrestrictionofthecausalfoodorfoodsisPatientswithahistoryoflaryngealswellingorres-piratorycompromiseshouldavoidrawfoodsstrictlyandbepre-scribedanepinephrineautoinjector.Asubsetofpatientswithpollen-foodallergysyndrometreatedwithhigh-dosepollensub-cutaneousimmunotherapymightexperiencecompleteresolutionorsigniÞcantimprovementinsymptoms,buttheutilityofimmu-notherapyOASisanareathatmeritsfurtherstudy.SummaryStatement51:Theclinicianshouldunderstandthevariousclinicalpresentationsoftheseconditions(ie,FPIES/proctocolitis/enteropathy),educatepatientsandcareprovidersaboutcommonfoodtriggers,andrecommendstrictfoodavoid-anceofallergenicfoodsforsymptommanagement.[Strengthofrecommendation:Strong;CEvidence]ThemanagementofnonÐIgE-mediatedfoodallergyreliesonstrictavoidanceofdietaryfoodproteinandattentiontoadequatenutrition.Pharmacologicagentsarenotrecommendedfortreatmentofchronicsymptoms.ThemostcommonfoodallergensinFPIES/proctocolitis/enteropathyarecowÕsmilkandsoypro-Thereactivitytobothfoodscancoexistinupto50%ofaffectedsubjects.InpatientswithFPIES,solidfoods,includingcerealproteins,suchasriceandoat,egg,Þsh,andpoultry,havebeenreportedinchildren,whereasshellÞshandmolluskshavebeenreportedinadults.Nutritionalconsul-tationmightbenecessarytoestablishprinciplesofavoidance,aswellastoensureanutritionallycompletediet.InfantswithJALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL FPIEStomultiplefoodsareatriskoffeedingdisorders,likelybecauseofbothtraumaticexperiencesassociatedwithacutereac-tionsandreluctanceofparentstointroducenewfoods,andmightbeneÞtfromfeedingtherapy.Hypoallergeniccasein-basedfor-mulaistoleratedbythemajorityofpatients;however,10%to15%mightrequireanaminoacidÐbasedformula.withmilk/soyFPIESareusuallyasymptomaticwhilebeingbreast-fed,althoughifsymptomsarenotedduringbreast-feeding,strictmaternaldietaryavoidanceofthecausalallergenshouldbeimplemented.Incontrast,upto60%ofinfantswithallergicproctocolitishavesymptomswhilebeingbreast-fed.Whenappropriatefoodallergeniseliminatedfromthematernaldiet,theresolutionoffreshbloodisobservedwithinafewdaysandthedisappearanceofoccultbloodisobservedusuallywithin5to7days.ItisunknownwhetherchildrenwithnonÐIgE-mediatedfoodallergytolerateextensivelyheated(baked)milkandegg.SummaryStatement52:UsevolumereplacementtherapyfortheacutecaremanagementofpatientswithFPIES.[Strengthofrecommendation:Strong;BEvidence]ThephysicianshouldrecognizethatacuteFPIESisamedicalemergencywithuptoa15%riskofhypovolemicshock.Theacuteonsetofsevererepetitiveemesiswithin1to3hoursaf-terfoodingestion,lethargy,andduskyappearance,togetherwithlackofcutaneousandrespiratorysymptoms,isconsistentwithFPIES.Diarrheamightfollowwithin4to6hours.TheÞrstlineoftreatmentisvigorousintravenoushydrationwithrapidnormalsalineboluses.EpinephrinecanbeusedincaseofseverehypotensionbutisnothelpfulasaÞrst-linetreatment,unlikeinAsingledoseof1to2mg/kgintravenousmeth-ylprednisolonecanbeusedinsomepatientswithprotractedsymptoms,althoughefÞcacyhasnotbeenestablished.ArecentsmallcaseseriesofchildrenwithFPIESsuccessfullytreatedwithondansetronduringasupervisedOFCsuggestedthatondan-setronmightbeusefulformanagingacuteFPIESreactions.patientswithmilderreactions,oralrehydrationmightbeBecauseFPIESisunderrecognizedbyprimarycareandemergencydepartmentprovidersandisthereforefrequentlymismanaged,aletterdescribingmanifestationsofFPIESandmanagementofacutereactionsshouldbeprovidedtopatients.AtemplateofsuchanFPIESemergencylettercanbefoundinanarticlebySichererandonline(http://www.iaffpe.org/).Inpatientswithproctocolitisandenteropathy,symp-tomsareusuallychronic,andthereislowriskforacutereactions.Managementincludesdietaryavoidanceofculpritfoods.SummaryStatement53:SeepatientswithFPIESandallergicgastrointestinaldisordersatregularintervalsandconsiderrechal-lengeinanappropriatemedicalfacilitybasedonthenaturalhis-toryofthespeciÞcdisorder.[Strengthofrecommendation:Strong;CEvidence]FoodsinducingFPIESshouldnotbechallengedathomebecauseoftheriskofhypotensionandshouldbechallengedinamedicalfacility.Althougharecentpopulation-basedstudyreportedsuccessfulmanagementofreactionsduringOFCswithoralrehydration,itisadvisabletohaveintravenoushydrationreadilyavailableincaseofseverereactions.Therearenobio-markerspredictiveofthenaturalhistoryortherisksoflife-threateningreactionsinpatientswithFPIES.Timingofthefollow-upchallengesisbasedonthenaturalhistory,usuallyabout12to18monthsafterthemostrecentacutereaction.However,morefrequentrechallengeattemptsmightbeappropriateinyoungchildrenwithmilkandsoyallergyandnohistoryofsevere/life-threateningFPIES.APTsarenothelpfulfortimingfoodreintroductionattempts.Introductionoffoodsavoidedonaprecautionarybasisandwithoutpriorreactionscanbeattemptedcarefullyathome.Itisprudenttostartfromfoodsthatbelongtothesamegroupasalreadytoleratedfoods,suchassoyforlegumesorriceforcerealgrains.Ifnofood-sIgEisdetected,reintroductionoftheoffendingfoodinpatientswithproctocolitisandenteropathyisusuallyperformedathome.IffoodsIgEisdetected,physician-supervisedchallengemightbenecessarybecauseofthepotentialprogressionofthede-layedgastrointestinalsymptomstoimmediateanaphylacticSummaryStatement54:ConsiderserialtissuebiopsiesaspartofdiseasemanagementinpatientswithEoE.SymptomsaloneorendoscopywithoutbiopsycannotbeusedasanaccurategaugeofEoEdiseaseactivity.[Strengthofrecommendation:Strong;CCurrentprospectiveclinicalEoEtrialshaveusedhistologyasoneprimaryendpointvariable.Studiesshowthatsymptoms,ascurrentlyevaluated,donotprovideanadequatesurrogatemarkerofesophagealdiseaseactivityanddonotserveasanadequatesoledeterminantforclinicaldecisions.tomsareanimportantcomponentofEoEmanagement,buttherearenovalidatedEoEsymptomoractivityindexesavail-TherecanbediscordancebetweenhistologyandsymptomsinpatientswithEoEbecauseoftheintermittencyofsymptomsandbehavioralchangesthatcancompensateforsymp-tomsofdysphagia.Althoughavalidatedendoscopytoolhasbeendevelopedwithgoodinterobserveragreementforendo-scopicÞndingsoffurrows,edema,rings,andexudates,copywithoutbiopsydoesnotprovideanadequatediseaseactivitymarker.ThereiscontroversyregardingthebesttreatmentendpointvariableforEoEresolution,buthistologicevaluationisSummaryStatement55:ConsiderassessmentforaeroallergensensitizationbecauseEoEcanbetriggeredbyaeroallergensinhu-mansubjectsandanimalmodelsandtheremightbeaseasonalitytoEoEdiagnoses.[Strengthofrecommendation:Moderate;DControlofotherconcurrentallergicdiatheses,includingallergicrhinitis,asthma,eczema,andimmediatehypersensitivitytofoods,isrecommendedinpatientswithEoE.AnimalmodelsclearlydemonstratethatmurineEoEcanbetriggeredbyAspergillusspecies,housedustmite,andcockroachextracts.PollenscanalsodrivehumanesophagealinÞltrationofeosinophils,EoEcanremitandrecurduringthepollenseason,andaeroallergenimmuno-therapycaninduceEoEremission.337-340AlthoughtherecanbeseasonalitytoEoEdiagnosis,morestudiesarerequiredtoprovidedirectevidencethatpatientswithEoEgivenadiagnosisinagivenseasonhaveapredictedaeroallergensensitizationpattern.Cross-reactivitytopollensmightbeimportantinEoEpathogenesis.341ItispossiblethatinsomepatientstherewillbespontaneousEoEremissionandrecrudescenceinandoutofthepollenseason.Assuch,aeroallergenavoidancemeasuresshouldberecommended,andtreatingphysiciansmightwanttoconsiderseasonalityinthecontextofaeroallergensensitizationwhenassessingesophagealbiopsyspecimens.100SummaryStatement56:ConsiderfoodallergyevaluationwithbothskinprickandpatchtestingforEoEtoruleoutpossiblefoodtriggers.RememberthatpositiveserumspeciÞcIgElevels,foodJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL SPTresponses,andfoodpatchtestresultsarenotsufÞcienttodi-agnosefoodtriggersforEoE.[Strengthofrecommendation:Moderate;CEvidence]AlthoughEoEclearlycanbeafood-triggeredprocessinbothhumansubjectsandanimalmodels,currenttestingmodal-itiesarenotsufÞcienttoreliablypredictEoEfoodtriggers.HighratesofpositiveIgEtestresultstofoodsoccurinpatientswithEoE,butskinpricktestingpredicted13%ofcausativefoodsinadultsandchildren,andcombinationprickandpatchtestingpredicted44%ofcausativefoodsinchildren.FoodpatchtestinghasnotbeenstandardizedorvalidatedinpatientswithEoE.However,positivefoodpatchtestresultsoccurin30%to95%ofchildrenandadultswithEoE.InonestudytheNPVsofcombinedprickandpatchtestingvarybythefoodtested(42%formilkandupto92%forotherfoods).Thishasnotbeenuniformlyreproducible.Assuch,foodtestingmightbeusefulduringfoodreintroductionaftereliminationsinpatientswithEoE.Inaddition,IgEtestingtofoodsshouldbeusedinpatientswithEoEtoassessthosepatientswhomightrequireamedicallysupervisedfoodchallengetoexcludeIgE-mediatedclinicalreactionsonfoodreintroduction.Thecurrentlyreportedratesoffood-inducedanaphylaxisarehigherinpatientswithEoEthaninthegeneralpopulation.researchisrequiredtoassesswhetherCRDorserumspeciÞcfoodIgEisvaluableinguidingdietaryeliminationinpatientswithEoE.SummaryStatement57:Considertheuseoftargetedorempiricfood-eliminationdietsoraminoacidÐbaseddietsforsuccessfulEoEtherapy.[Strengthofrecommendation:Strong;BEvidence]AlthoughaminoacidÐbasedformulashavethehighestsuccessrates(ofteninthe90%range)andthelargesteffectsoninßammatorycontrol,elementaldietscanbedifÞculttoadministerwithoutnasogastricorgastrostomytubeplace-AminoacidÐbasedformulasarealsoeffectiveinadults,butadherenceisdifÞcult.Empiriceliminationofcommonfoodantigens,speciÞcallymilk,wheat,egg,soy,peanuts,treenuts,Þsh,andshellÞsh,isarecommendedEoEtherapywithreportedhistologicresponseratesof53%to82%inadultsandchildren.ThemostcommonfoodallergensinadultandpediatricpatientswithEoEaremilk,wheat,andegg,andtheadditionofmilkeliminationincombinationwithaprick/patch-basedeliminationdiethasbeenreportedtohave77%histologicsuccess.SummaryStatement58:ConsidertheuseofswallowedtopicalesophagealcorticosteroidsforsuccessfulEoEtherapy.[Strengthofrecommendation:Strong;AEvidence]AnumberofprospectivetrialsinadultandpediatricpatientswithEoEdemonstratehistologicefÞcacyoftopicalesophagealcorticosteroidsatratesof50%togreaterthan80%.Usedtherapiesincludepuffedßuticasoneorciclesonidetothebackofthethroatfollowedbyforcefulswallowmetered-doseinhalers.Swallowedviscoussuspensionofbudeso-nideisalsosuccessfulEoEtherapyandmightbemoreeffectivethannebulized/swallowedbudesonide.Theoptimaldura-tionoftherapyrequiresadditionalstudies,butEoEisachronicdiseaseinmostadultsandchildren.Whenthetopicalcorticoste-roiddoseisdecreasedinadultswithEoE,inßammationandÞbrosisreturn,althoughtoalesserextentthanafterplacebo.Oraland/oresophagealcandidiasisisapotentialsideeffectoftopicalcorticosteroidsandoccursinupto15%ofsubjects.Inaddition,thelong-termsafetydataonesophagealcorticosteroidsrequireclariÞcation.(Theuseofleukotrieneantagonistsandoralcromolyn[Gastrocrom]arenotrecommended.)SummaryStatement59:Referraltoagastroenterologistforesophagealdilationisrecommendedforhigh-gradestenosisbutdoesnotprovideinßammatorycontrol.[Strengthofrecommen-dation:Moderate;CEvidence]SigniÞcantsymptomcontrolisachievedafterdilation.Com-plicationsincludechestpain(5%),perforation(0.8%),andbleedingrequiringbloodtransfusion(reportedinonly1SummaryStatement60:AdministeroralcorticosteroidsforEGEasthepreferredtherapy.[Strengthofrecommendation:Weak;CEvidence]ThemostsuccessfuldocumentedtreatmentforEGEisoralcorticosteroidtherapy,andthisisrecommended,butuseofcorticosteroidsshouldbejudiciousandasshorttermaspossible.ThereareanumberofcasereportsthatdocumentEGEclearancewithmilkelimination,andalimitedtrialofaminoacidÐbasedoreliminationdietscanbeconsidered.Resultsofimmediatehypersensitivityskintestingareusuallynegative.Thereisnoclearutilityofmontelukastindiseasemanagement.CurrentdatashowthatEGEcanhaveasingleßare,recurringorcontin-uouscourseswiththesubserosalformhavingsingleandrecurringßares,whereasmucosalandmuscularvariantscanpresentwithanyofthe3courses.SECTIONVIII:EMERGINGTHERAPIESFORFOODALLERGYSummaryStatement61:Althoughimmunotherapeuticap-proaches,suchasoralimmunotherapy(OIT),inclinicaltrialsshowpromiseintreatingfoodallergy,theyarenotreadyforim-plementationinclinicalpracticeatthepresenttimebecauseofinadequateevidencefortherapeuticbeneÞtoverrisksoftherapy.[Strengthofrecommendation:Strong;AEvidence]Severalnewtherapeuticapproachesarebeingtestedinclinicaltrials,withthemajorfocusonIgE-mediatedfoodallergy.ofthesetherapiesarereadyforclinicalcarebecauseoftheuncon-trollednatureofmosttrials,smallnumberofsubjectsstudies,se-lectionbias,anduncertainsafetyproÞles.OIThasbeenstudiedmostextensivelyandshowntobeeffectiveforseveralfoodallergens(eg,milk,egg,andpeanut)forprovidingprotectionagainstlife-threateningreactionsduringtherapy(desensitization)andforthepotentialofdevelopingtolerancewhentherapyisdis-Althoughpromising,OITisalsoassociatedwithfrequentadverseallergicreactions,andthusitisnotreadyforwidespreadclinicaluse.Dietscontainingextensivelyheated(baked)milkandeggmightbeanalternativeapproachtoOITinapproximately70%ofaffectedpatientsifÞndingsofefÞcacyaremaintainedwithimprovedsafetyproÞles.gualimmunotherapyhasshownearlypromisingresultstodecreasesensitizationwithlowsideeffectproÞlesduringtreat-mentforpeanutallergy,butprotectivedesensitizationissigniÞ-cantlylessthanwithOIT.InlimitedstudiestherapiesusingmodiÞedantigens,epicutaneouslyadministeredallergenimmunotherapy,orChineseherbaltherapycouldalsorepre-sentsafeandefÞcientalternativesoradjunctivetherapiesinthefuture.Additionally,treatmentwithanti-IgEmAbsusedaloneorincombinationwithotherformsofimmunotherapymightin-creasethresholddosesneededtostimulateanallergicreactionandprovideenhancedsafetyproÞlesforpatients.JALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL therapieswithantiÐIL-5,anti-TNF,andanti-IgEhavehadvaryingsuccessandarenotrecommendedforroutineuseinpatientswithEoE.Othertherapies,suchasazathioprine,methotrexate,oralcromolyn,leukotrieneantagonists,andothernonspeciÞcimmunomodulators,havenotdemonstratedabeneÞ-cialeffectondiseasemanifestationsofEoE.SECTIONIX:MANAGEMENTINSPECIALSETTINGSTooptimallymanagepatientswithfoodallergy,theclinicianandtherestofthehealthcareteammustbeeducators,discussingavoidanceoftheallergenandtheeffectoflocationsatwhichtheallergicreactionmightoccur,suchasschools,homesoffriendsorrelatives,restaurants,andotherpublicplaceswithregardtoimplementationofthetreatmentplan.Insomecommunitiesthereareteamsthatincludecaregiversandhealtheducators,aswellasphysiciansandfamilies.Educationisanongoingprocessthatrequiresreviewduringeachvisitforbothchildrenandadults.Asnotedabove,teamsofeducatorsmightincludenurses,disease-speciÞceducators,andpersonstohelpwithfeeding/nutritionissues.SpeciÞcrecom-mendationsdependonthephysicalanddevelopmentalageofthepatientatthetimeoftheinitialdiagnosisandchangesovertime.Youngchildrenmustbesupervisedandtaughttosharetoysbutneverfood,whereasolderchildrenmustlearntoaskbeforetheyeatanythingnotsuppliedbyparentsorotherregularcaregivers(andsometimessuppliedbyfamilymembersincludingparentsandgrandparents).School-agedchildrenshouldbetaughttoreadlabelsthemselvesandaskaboutingredientswithparentalhelpandsupervision.Duringadolescence,thetransitiontoself-carebecomescrucial,sothatteenscanprotectthemselveswhentheyleavehome.Thistransitioniscriticalbecausetheremightbetripsinhighschoolandcertainlycollegewhentheyarefarfromhome.Evenadultpatientsneedongoingreinforcement,sothattheydonotbecomecarelessregardingingredientsinfoodseatenawayfromhomeandcarelessaboutcarryingself-injectableepineph-rine.Thisisparticularlyimportantforadult-onsetfoodallergytofoodspreviouslyeaten,suchasshrimp.Mostcaregiverswillrecognizetheimportanceofeducatingpatientsaboutavoidanceissuesinthehome,atschool,andinSchoolsandchildcarecentersshouldhavepoliciesandprogramsforfacilitatingavoidanceoffoodaller-Staffeducationshouldincludelabelreadingandin-formationaboutcross-contact/contaminationduringfoodpreparation,propercleaningofutensils,andpotentialallergensinclassprojects.EducationofrestaurantmanagementandpersonnelisasigniÞcantproblemandhasbeguntorespondtoconcernsvoicedbymultiplemedicalandindustrygroups.Inaddition,thereareanumberofothersitesthatmustbeconsideredanddiscussed.Theseinclude(butarenotlimitedto)religiousschoolsettings,sportspractices,orafterschoolclubs,wheresnacksareoftenmadeavailablewithouttheabilitytochecktheingredients.Evenhospitalizedpatientsmustmaketheirfoodallergiesknowntotheirphysiciansandnursesandthedietary/kitchenstaff.Hospitalpersonnelshouldaskaboutfoodallergy,butpatientsmustensuretheirownsafetybyreportingtheseallergiesandcarefullyinspectingtheirmeals.Campsmightnothaveadequatesystemsforinquiringaboutfoodallergies(andtheymightnothaveadequateactionplans,seebelow).Transportationbyvariousmeansalsopresentsariskofaccidentalexposure.Airtravelhasreceivedthemostattention,butlongrailtrips(especiallyinforeigncountries)andcruiseshipspresenttheirownsetofrisksthatmustbeanticipated.Inthelastfewyears,therehasbeenanincreaseinthenumberoforgantransplantrecipientswhohavehadreactionstofoodstowhichthedonorwasallergic.BecausedonorsÕnearestofkinareusuallyinvolvedinpermissiontodonateorgans,queriesaboutthedonorÕsfoodallergiesshouldbepartoftheinformationgathered.ThisinformationshouldberelayedtotherecipientandtherecipientÕsfamilysothatproperprecautionscanbeunder-Cliniciansmusteducatetheirpatientswithfoodallergyaboutoptimaltreatmentofaccidentalingestionsandreinforcethefactthatonlyself-injectableepinephrineislife-savingforIgE-mediateddisease.Thereisonly1life-savingtreatmentforallergicreactiontofoods:injectableepinephrine.Inthevastmajorityofsit-uations,thisinvolvesself-injectableepinephrinewithanautoin-jector.Althoughitisimpossibletoundertakeacontrolledtrialoftreatmentchoicesforanaphylacticreactions,thereisnoevi-dencethatantihistaminescanbelife-saving,andtherearereportsfromclinicalseriesofpatientsdyingdespitetheadministrationofanantihistamine,thusreinforcingthesentinelplaceofself-injectableepinephrine.Cliniciansshouldcontinuetoeducatepar-entsorpatientsabouttheproperuseofepinephrineautoinjectorswhentheycometotheclinicforavisittoensuretheirabilitytousethesedevicescorrectly.Amajorissueintheeducationofpatientsandfamiliesisrecognitionofanallergicreaction.Asnotedpreviously,thereareanumberofsituations/circumstancesinwhichaccidentalin-gestionscanoccur.RecognitionthatareactionisoccurringrequiresvigilanceandawillingnessnottodenythesymptomsthathavebegunorassumethatthepatientwillbeabletoÔÔtoughitout.ÕÕPatientsshouldbetaughtthataseverereactionisadistinctpossibility.Incasesinwhichapreviouslife-threateningreactionhasoccurred,self-injectableepinephrinemustbegivenpromptly,andthepatientshouldimmediatelyseekemergencymedicalIdentiÞcationjewelryforpatientswhomighthaveafood-inducedreactionandmightneedinjectedepinephrineisrecommendedbecausethisremindsthepatientandalertsothersoftheirreactivity.Adolescentsandyoungadultsshouldbetaughtnevertobealoneorgohomealone(eg,includingdormitoriesandapart-ments)iftheythinktheyarehavingareaction.Theyshouldalwaysstaywithsomeoneorgotothehospital.Theyshouldalwayschecktoensurethatsomeoneisavailableand,ifnot,Þndsomeonetobewiththemuntilitisclearthatanypossibledangerhaspassed,suchasabout4hoursaftersymptomsclear.Theyshouldneverdrivealoneifsymptomsarepresent.SummaryStatement62:Developawrittenactionplanfortreat-mentofallergicreactionstofoodforadultsandchildren.[Strengthofrecommendation:Moderate;DEvidence]Patientswithfoodallergyshouldhavewrittenavoidanceandtreatmentplansthatchangeastheyage.Thetreatmentplanshouldbeseparatefromtheavoidanceplan,sothatintheeventofareaction,thetreatmentprotocolcanbeidentiÞedquicklyandaccuratelyandactioncanbetakenpromptly.Therearenumeroushandoutsavailablefromvarioussourcesthatdetailthemannerinwhichavoidanceisaccomplished(seetheWebsitelistbelow).TheseshouldbemadefreelyJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL availabletopatientswithfoodallergy.Thereshouldbeaprovisionforsubstitutionofsafefoodsinallsettings.Ingredientlabelsshouldbeeasilyavailableandregularlyreviewed.Careshouldbetakentopreventcross-contamination/cross-contact,andthisincludesinstructionsforavoidanceduringcraft,cook-ing,andscienceprojects.Treatmentprotocolsshouldbedesignedtopreventdelaysinrecognitionandtreatmentofsymptoms.Theseplansshouldbesimplesothatsymptomscanberecognizedquickly,andtheyshouldbereadilyavailableintheeventofareaction.Indaycarecentersandschoolstheplansshouldbereviewedperiodicallyforeachpatient.Thereshouldbeaphysician-prescribedprotocol,andthemedicationshouldbereadilyavailableandnotlockedinaSeveralstateshavestandardprotocolsthataretobeusedintheirschools.Thereisalsoacommonlyusedprotocolavailablehttp://www.foodallergy.orghttp://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Libraries/Anaphylaxis-Emergency-Action-Plan.pdfManyadultsdonothaveawrittenprotocolfortreatmentoftheirfood-inducedallergicreactions;however,itshouldbecleartoalladultswithfoodallergyandtheirfamilymembershowtorespondtotheonsetofsymptomsandwhenself-injectableepinephrineshouldbeadministered.SummaryStatement63:Inquireaboutandaddressbehavioralchangesbecauseofbullyinginpatientswithfoodallergy.Thisin-quiryshouldincludeadultsandchildren.[Strengthofrecommen-dation:Strong;DEvidence]Animportantandoftenneglectedaspectoffoodallergyeducationinvolvesbullyingofthechildwithfoodallergy.Thisisaconsequentialproblemthatcanleadtoongoingemotionalproblems,schoolavoidance,andactualharm.Bullyingshouldnotbetolerated.Itshouldbepromptlyrecognizedandreported,andtheconsequencesshouldbesigniÞcant.Oftentheissueislackofeducationoftheperpetratorandhisorherfamily.SummaryStatement64:Teachpatientsthatingestion,ratherthancasualexposurethroughtheskinorcloseproximitytoanallergen,isalmosttheonlyroutefortriggeringsevereallergic/anaphylacticreactions.[Strengthofrecommendation:Strong;CIntimaterelationshipsbegintopresentriskinadolescenceandthereafter.Precautionsforintimatekissingshouldbediscussedthoroughlywithadolescentsandadultsandshouldbereinforcedbyparentsofteensanddirectlybyphysicianstoadultpatientsatregularintervals.Exposureduringincidentalenvironmentalcon-tactcanoccur,butthecircumstanceswoulddeterminewhetherareactionwouldoccur.Casualskincontactisunlikelytocauseanaphylaxis,ashasbeendemonstratedinstudiesinwhichpatientswithpeanutallergyhavebeendirectlyexposedtopeanutincontrolledsettings,althoughitmightplayaroleinmaintainingsensitization.Thisstudyexposedpatientswithhigh-levelpeanutallergythroughbothcontactandinhalation.Althoughitcannotbedirectlyextrapolatedtootherpopulations,theresultsareAlthoughtherearefamiliesandpatientsthatareveryconcernedaboutcasualcontacttriggeringsevereallergicreactions,therearefew,ifany,well-documentedcasesofthisexposurecausingmortality.Themostimportantpointforcaregiverstomakewithpatients/parentsisthatpatientswithfoodallergymustlearntoÔÔliveintheworld.ÕÕThisissuemustbediscussedinanongoingprocessthatentailsmultiplemeetingswithfamiliesand,onoccasion,mighteveninvolvein-ofÞcecasualexposure(aswasundertakeninthestudybySimonteetal).Havingsuchmeetingstoaddresstheseissuesisstronglyencouragedbecausethereislikelynogoodsubstituteformakingfamiliesmorecomfortable.REFERENCESAmericanCollegeofAllergy.Astham&Immunology.Foodallergy:apracticeparameter.AnnAllergyAsthmaImmunol2006;96(suppl2):S1-68.(IV)BoyceJA,AssaÕadA,BurksAW,JonesSM,SampsonHA,WoodRA,etal.GuidelinesforthediagnosisandmanagementoffoodallergyintheUnitedStates:reportoftheNIAID-sponsoredexpertpanel.JAllergyClinImmunol2010;126(suppl):S1-58.(IV)ChafenJJ,NewberrySJ,RiedlMA,BravataDM,MaglioneM,SuttorpMJ,etal.Diagnosingandmanagingcommonfoodallergies:asystematicreview.JAMA2010;303:1848-56.(Ia)SichererSH.Epidemiologyoffoodallergy.JAllergyClinImmunol2011;127:594-602.(III)SichererSH,Munoz-FurlongA,GodboldJH,SampsonHA.USprevalenceofself-reportedpeanut,treenut,andsesameallergy:11-yearfollow-up.JAllergyClinImmunol2010;125:1322-6.(III)BranumAM,LukacsSL.FoodallergyamongchildrenintheUnitedStates.Pe-diatrics2009;124:1549-55.(III)RonaRJ,KeilT,SummersC,GislasonD,ZuidmeerL,SodergrenE,etal.Theprevalenceoffoodallergy:ameta-analysis.JAllergyClinImmunol2007;120:638-46.(III)ZuidmeerL,GoldhahnK,RonaRJ,GislasonD,MadsenC,SummersC,etal.Theprevalenceofplantfoodallergies:asystematicreview.JAllergyClinImmu-nol2008;121:1210-8.e4.(Ia)GuptaRS,SpringstonEE,WarrierMR,SmithB,KumarR,PongracicJ,etal.Theprevalence,severity,anddistributionofchildhoodfoodallergyintheUnitedStates.Pediatrics2011;128:e9-17.(III)Ben-ShoshanM,HarringtonDW,SollerL,FragapaneJ,JosephL,StPierreY,etal.Apopulation-basedstudyonpeanut,treenut,Þsh,shellÞsh,andsesameal-lergyprevalenceinCanada.JAllergyClinImmunol2010;125:1327-35.(III)OsborneNJ,KoplinJJ,MartinPE,GurrinLC,LoweAJ,MathesonMC,etal.Prevalenceofchallenge-provenIgE-mediatedfoodallergyusingpopulation-basedsamplingandpredeterminedchallengecriteriaininfants.JAllergyClinIm-munol2011;127:668-76.e1-2.(III)LuccioliS,RossM,Labiner-WolfeJ,FeinSB.Maternallyreportedf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FIGE1.Categoriesoffoodreactions.JALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL TABLEE1.Foodallergencross-reactivityReference(s)FoodgroupMajorallergensSensitization(%)reactivity(%)Comments305-308AvianandMilk:cowvsother20-1004-92Highcross-reactivitywithgoatÕs,sheepÕs,andbuffaloÕsLowcross-reactivitywithmareÕs,donkeyÕs,andcamelÕsMilkvsbeef/meatSensitizationtoBSAisapredictor.Seventy-threepercentto79%ofchildrenwithbeefallergyarereactivetocowÕsmilk.Egg:henvsotherCommonÑCross-reactivityvariesamongspeciesbutiscommon.Eggvschicken/meatBird-eggsyndrome:sensitizationto-livetin33,314-316ShellÞshShrimpvsothercrustaceanCrustaceavsMolluscaMolluscavsMolluscaTropomyosinsarepanallergensthatalsoareresponsibleforcross-reactionstocrustaceansinthosewithdustmiteandcockroachallergy.33,317-320FishCodÞshvsotherÞsh5-10030-75Gadc1(codÞshparvalbumin)isapanallergen.61,321-323TreenutsTreenutvsothertreenut9212-37*HigherserumIgEcorrelationsbetweencashewandpis-tachioandbetweenpecanandwalnut321,322Treenutsvspeanut(legume)59-8633-34*HighersIgEcorrelationswithalmondandhazelnut57,324-327LegumesPeanutvssoy(other)19-793-5(28-30)Sensitizationtolentilsandchickpeasmightbeassociatedwithincreasedchanceformultiplelegumeallergy.328,329CerealsWheatvsother47-8821Mostavailabledataarefrompatientswithatopic*PercentagebasedonreportedclinicalreactionsandnotsystematicallyevaluatedbyusingDBPCFCs.DBPCFCdataforlupinechallengeinpeanut-sensitizedpatients.JALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL TABLEE2.SystemsandexamplesofsymptomsinvolvedinacuteIgE-mediatedreactionstofoodsErythema/ßushingContacturticariaTearingConjunctivalinjectionPeriorbitaledemaRespiratorytractPruritusNasalcongestionRhinorrheaLaryngealedemaLowerWheezingDyspneaChesttightness/painOralpruritusOralangioedema(lips,tongue,orpalate)ColickyabdominalpainCardiovascularTachycardiaLossofconsciousness/faintingMiscellaneousSenseofimpendingdoomUterinecramping/contractionsJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL TABLEE3.PredictivevalueofIgEtestinginpositiveornegativeOFCresults�95%Positive50%NegativesIgESPTsIgESPTwhealEggwhite�_�_2ifagey-32;倀___CowÕsmilk吐_吐_5ifagey
-32;倀__吐_吐__historyofprior_nohistoryofpriorreaction_吐_JALLERGYCLINIMMUNOLVOLUME134,NUMBER5SAMPSONETAL TABLEE4.Pollensandcross-reactivefoodsinpatientswithPollen/plantFruit/vegetableApple,cherry,apricot,carrot,potato,kiwi,hazelnut,celery,pear,peanut,soybeanMelon(eg,cantaloupeorhoneydew),bananaKiwi,tomato,watermelon,potatoCelery,fennel,carrot,parsleyBanana,avocado,chestnut,kiwi,Þg,apple,cherryJALLERGYCLINIMMUNOLNOVEMBER2014SAMPSONETAL